Oxazolidinone combinatorial libraries, compositions and methods of preparation

ABSTRACT

Oxazolidinones and methods for their synthesis are provided. Also provided are combinatorial libraries comprising oxazolidinones, and methods to prepare the libraries. Further provided are methods of making biologically active oxazolidinones as well as pharmaceutically acceptable compositions comprising the oxazolidinones. The methods of library preparation include the attachment of oxazolidinones to a solid support. The methods of compound preparation in one embodiment involve the reaction of an iminophosphorane with a carbonyl containing polymeric support.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/641,396, filed Aug. 17, 2000; which is a divisional of U.S. patentapplication Ser. No. 09/235,771, filed Jan. 22, 1999, issued as U.S.Pat. No. 6,239,152; which is a continuation in part of U.S. patentapplication Ser. No. 09/086,702, filed May 28, 1998, now abandoned; andwhich in turn claims the benefit of the following U.S. patentapplication Ser. No. 09/012,535, filed Jan. 23, 1998, now abandoned;under 35 USC 119(e)(i), incorporated herewith in their entirety.

FIELD OF THE INVENTION

The present invention is directed to oxazolidinones; oxazolidinonecompositions; oxazolidinone combinational libraries; and methods fortheir preparation and use.

BACKGROUND ART

Oxazolidinones are compounds where an amine group and a hydroxyl groupon adjacent carbon atoms have been cyclized to form a 5-membered ringcontaining a carbonyl group. Certain oxazolidinones have been shown toexhibit a variety of biological activities. For example, someoxazolidinones are inhibitors of monoamine oxidase-B, an enzymeimplicated in Parkinson's disease. See, for example, Ding et al., J.Med. Chem. 36:3606-3610 (1993).

A a ten step synthesis of oxazolidinone antibiotics has been described.U.S. Pat. No. 5,547,950. A four step synthesis of the antibacterialcompound U-100592 also has been reported; Schauss et al., TetrahedronLetters, 37:7937-7940 (1996). A five step preparation ofenantiomerically pure cis- andtrans-N-(propionyl)hexahydrobenzoxazolidin-2-ones further was reported.De Parrodi et al., Tetrahedron: Asymmetry, 8:1075-1082 (1997).

Scientists have reported that certain oxazolidinone derivatives exhibitbeneficial antibacterial effects. For instance,N-[3-[3-fluoro-4-(morpholin-4-yl)phenyl]2-oxooxazolidin-5(s)-ylmethyl]acetamide (below) has been reported to be useful for the treatment ofbacterial infections. Lizondo et al., Drugs of the Future, 21:1116-1123(1996).

The synthesis of the oxazolidinone antibacterial agent shown below hasbeen reported. Wang et al., Tetrahedron, 45:1323-1326 (1989). Thisoxazolidinone was made using a process that included the reaction of ananiline with glycidol to provide an amino alcohol, and thediethylcarbonate mediated cyclization of the amino alcohol to afford anoxazolidinone.

The synthesis of oxazolidinone antibacterial agents, including thecompound shown below has been reported. U.S. Pat. No. 4,705,799. Theprocess used to make the compound shown below included a metal mediatedreduction of a sulfonyl chloride to provide a sulfide.

The synthesis of oxazolidinone antibacterial agents, including thepyridyl compound shown below has been reported. U.S. Pat. No. 4,948,801.The process used included an organometallic mediated coupling of anorganotin compound and an aryl iodide.

Synthetic routes to oxazolidinones often allow a chemist to produce onlyone compound at a time. These laborious methods can provide a limitednumber of compounds for evaluation in a biological screen. These methodscannot, however, provide the number of compounds required to supply ahigh-throughput biological screen, an assay technique whereby theactivity of thousands of drug candidates, for example, per week, may beanalyzed. This limitation on compound production is of practicalimportance since high-throughput screens are desirable and efficient forthe discovery of new drugs.

SUMMARY OF INVENTION

Provided are oxazolidinones and combinatorial libraries, compositionscomprising oxazolidinones, as well as methods of their synthesis anduse. Using the methods provided herein, one of skill in the art canrapidly produce the large number of compounds required forhigh-throughput screening.

In one embodiment, provided are methods for the solid phase synthesis ofoxazolidinones.

In one embodiment, the method comprises attaching an olefin to a solidsupport, oxidizing the olefin to provide an epoxide functionality,opening the epoxide with an amine and cyclizing the resulting aminoalcohol using a phosgene equivalent.

In another embodiment, the method comprises attaching an allylic amineto a solid support, oxidizing the olefin of the allylic amine to providean epoxide, opening the epoxide with an amine, and cyclizing theresulting amino alcohol using a phosgene equivalent.

In another embodiment, the method comprises attaching allylamine to asolid support, oxidizing the olefin of allylamine to provide an epoxide,opening the epoxide with an amine and cyclizing the resulting aminoalcohol using a phosgene equivalent.

In another embodiment, the method comprises attaching an olefin to asolid support, oxidizing the olefin to provide an epoxide, opening theepoxide with an amino acid and cyclizing the resulting amino alcoholusing a phosgene equivalent.

In another embodiment, the method comprises attaching an olefin to asolid support, oxidizing the olefin to provide an epoxide, opening theepoxide with an aromatic amine and cyclizing the resulting amino alcoholusing a phosgene equivalent.

Methods also are provided for the synthesis of oxazolidinonecombinatorial libraries.

In one embodiment, the method comprises attaching an olefin group to anarray of solid supports, oxidizing the individual olefin groups toprovide an array of solid support bound epoxides, opening the epoxideswith amine units, and cyclizing the resulting array of amino alcoholsusing a phosgene equivalent.

In another embodiment, the method comprises attaching an allylic amineto an array of solid supports, oxidizing the individual olefin groups toprovide an array of solid support bound epoxides, opening the epoxideswith amine units and cyclizing the resulting array of amino alcoholsusing a phosgene equivalent.

In another embodiment, the method comprises attaching allyl amine to anarray of solid supports, oxidizing the individual olefin groups toprovide an array of solid support bound epoxides, opening the epoxideswith amine units and cyclizing the resulting array of amino alcoholsusing a phosgene equivalent.

In another embodiment, the method comprises attaching an olefin to anarray of solid supports, oxidizing the individual olefin groups toprovide an array of solid support bound epoxides, opening the epoxideswith amino acid units and cyclizing the resulting array of aminoalcohols using a phosgene equivalent.

In another embodiment, the method comprises attaching an olefin to anarray of solid supports, oxidizing the individual olefin groups toprovide an array of solid support bound epoxides, opening the epoxideswith aromatic amine units and cyclizing the resulting array of aminoalcohols using a phosgene equivalent.

Provided are a variety of oxazolidinones and combinatorial librariesthereof. In one embodiment, the oxazolidinones have the structure:

where R₁ is selected from the group consisting of alkyl, heteroalkylaryl and heteroaryl; R₂ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl; aryl and heteroaryl; R₃ is selected fromthe group consisting of hydrogen, alkyl, heteroalkyl, aryl andheteroaryl; R₁ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl and heteroaryl; and R₁₂ is selected from the groupconsisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.

In another embodiment, oxazolidinones and combinatorial libraries areprovided wherein the oxazolidinones are of the structure 1b, wherein R₂,R₃, R₄ and R₅ are, independently, hydrogen, alkyl,

heteroalkyl, heteroaryl or an electron withdrawing group; R₆ is acyl orsulfonyl; and, R₁ is one of the following functional groups: C(O)NR₇R₈,wherein R₇ and R₈ are, independently, hydrogen, alkyl, heteroalkyl, arylor heteroaryl; C(O)OR₉, wherein R₉ is hydrogen, alkyl, heteroalkyl, arylor heteroaryl; C(O)R₁₀, wherein R₁₀ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; SR₁₁, wherein R₁₁ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; S(O)₂R₁₁, wherein R₁₁ is hydrogen, alkyl,heteroalkyl, aryl or heteroaryl; S(O)R₁₁, wherein R₁₁ is hydrogen,alkyl, heteroalkyl, aryl or heteroaryl; NR₁₂R₁₃, wherein R₁₂ and R₁₃are, independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, arylor heteroaryl; 2-oxazolyl, wherein R₁₄ is at the 4-position and R₁₅ isat the 5-position of the oxazolyl, and wherein R₁₄ and R₁₅ are,independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or anelectron withdrawing group; 2-aminothiazolyl, wherein R₁₆ is at the4-position and R₁₇ is at the 5-position of the thiazole, and wherein R₁₆and R₁₇, are, independently, hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or an electron withdrawing group; and, CH₂NR₁₈R₁₉, whereinR₁₈ and R₁₉ are, independently, hydrogen, alkyl, heteroalkyl, aryl,heteroaryl, acyl or sulfonyl.

All compounds disclosed herein can exist as different isomer formsincluding stereoisomers and enantiomerically pure forms, and all suchisomers and forms are within the scope of the invention. For example,while structure 1b is shown with the preferred embodiment of a S isomerat the 5 position of the oxazolidinone, the R isomer is within the scopeof the invention. Similarly, in all of the other oxazolidinonecompounds, in the case where a preferred stereoisomer is shown at the 5position of the oxazolidinone, both stereoisomers are within the scopeof the invention.

In one embodiment of structure 1b, R₁ is C(O)R₇R₈.

In another embodiment of structure 1b, R₁ is C(O)OR₉.

In another embodiment of structure 1b, R₁ is C(O)R₁₀.

In another embodiment of structure 1b, R₁ is SR₁₁.

In another embodiment of structure 1b, R₁ is S(O)₂R₁₁.

In another embodiment of structure 1b, R₁ is S(O)R₁₁.

In another embodiment of structure 1b, R₁ is NR₁₂R₁₃. In anotherembodiment, R₁ is NR_(x)(C═O)R_(y), wherein R_(x) and R_(y) areindependently hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl;

-   -   or R₁ is NR_(x)(SO₂)R_(y), wherein R_(x) and R_(y) are        independently hydrogen, alkyl, heteroalkyl, aryl, or heteroaryl        with the proviso that R_(y) is not H;

In another embodiment of structure 1b, R₁ is 2-oxazolyl, wherein R₁₄ isat the 4-position and R₁₅ is at the 5-position of the oxazole group.

In another embodiment of structure 1b, R₁ is 2-aminothiazolyl, whereinR₁₆ is at the 4-position and R₁₇ is at the 5-position of theaminothiazolyl group.

In another embodiment of structure 1b, R₁ is CH₂NR₁₈R₁₉.

In another embodiment of structure 1b, R₁ is C(O)NR₇R₈; and, R₃, R₄ andR₅ are hydrogen.

In another embodiment of structure 1b, R₁ is C(O)NR₇R₈; R₃, R₄ and R₅are hydrogen; and, R₂ is fluorine.

In another embodiment of structure 1b, R₁ is C(O)NR₇R₈; R₃, R₄ and R₅are hydrogen; R₂ is fluorine; and, R₆ is C(O)CH₃.

In another embodiment of structure 1b, R₁ is C(O)NR₇R₈; R₃, R₄ and R₅are hydrogen; R₂ is fluorine; R₆ is C(O)CH₃; and, R₇ is hydrogen.

In another embodiment of structure 1b, R₁ is C(O)NR₇R₈; R₃, R₄ and R₅are hydrogen; R₂ is fluorine; R6 is C(O)CH₃; R₇ is hydrogen; and, R₈ isheteroaryl.

A variety of methods of preparing combinatorial libraries comprisingoxazolidinones are provided.

In one embodiment, the method is for the preparation of oxazolidinones,such as those of structure 1b. The method comprises the steps of:attaching a plurality of aryl oxazolidinones to a plurality of solidsupports; functionalizing the 4-position of the aryl groups of theattached oxazolidinones; and, optionally, removing the oxazolidinonesfrom the solid supports.

In another embodiment, the aryl oxazolidinone is attached to a solidsupport through the reaction of an iminophosphorane with a carbonylcontaining resin to form an imine. In another embodiment, the aryloxazolidinone is attached to a solid support through the reaction of anamine with a carbonyl containing resin to form an imine.

In another embodiment, the aryl oxazolidinone is attached to a solidsupport through the reaction of an iminophosphorane with a carbonylcontaining resin to form an imine, and the imine is reduced to form anamine. In another embodiment, the aryl oxazolidinone is attached to asolid support through the reaction of an amine with a carbonylcontaining resin to form an imine, and the imine is reduced to form anamine.

Also provided are biologically active oxazolidinones and compositionscomprising biologically active oxazolidinones. For example, theoxazolidinones may have antibiotic activity.

In one embodiment, the biologically active oxazolidinones are of thestructure 1b.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is C(O)NR₇R₈.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2 oxazolyl containingR₁₄ at the 4-position and R₁₅ at the 5-position of the oxazole.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2-aminothiazolylcontaining R₁₆ at the 4-position and R₁₇ at the 5-position of theaminothiazole.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is C(O)NR₇R₈, and whereinR₃, R₄ and R₅ are hydrogen.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2 oxazolyl containingR₁₄ at the 4-position and R₁₅ at the 5-position of the oxazole, andwherein R₃, R₄ and R₅ are hydrogen.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2-aminothiazolylcontaining R₁₆ at the 4-position and R₁₇ at the 5-position of theaminothiazole, and wherein R₃, R₄ and R₅ are hydrogen.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is C(O)NR₇R₈, and whereinR₃, R₄ and R₅ are hydrogen, and further wherein R₂ is fluorine.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2 oxazolyl containingR₁₄ at the 4-position and R₁₅ at the 5-position of the oxazole, andwherein R₃, R₄ and R₅ are hydrogen, and further wherein R₂ is fluorine.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is 2-aminothiazolylcontaining R₁₆ at the 4-position and R₁₇ at the 5-position of theaminothiazole, and wherein R₃, R₄ and R₅ are hydrogen, and furtherwherein R₂ is fluorine.

In another embodiment, the biologically active oxazolidinones are of thestructure 1, wherein R₁ of the oxazolidinone is C(O)NR₇R₈, wherein R₇ ishydrogen and R₈ is 5-chloropyridine-3-yl, thiazole-2-yl,5′-(5-aminopyridine-2-yl)thiopyridine-3′-yl, or pyridine-3-yl; andwherein R₃, R₄ and R₅ are hydrogen; and further wherein R₂ is fluorine;and further wherein R₆ is C(O)CH₃.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b, wherein R₁ of the oxazolidinone is C(O)NR₇R₈, wherein R₇is hydrogen and R₈ is 5-chloropyridine-3-yl; and wherein R₃, R₄ and R₅are hydrogen; and further wherein R₂ is fluorine; and further wherein R₆is C(O)CH₂SMe.

In another embodiment, the biologically active oxazolidinones are of thestructure 1 wherein R₁ of the oxazolidinone is C(O)NR₇R₈, wherein R₇ ishydrogen and R₈ is 5-chloropyridine-3-yl; and wherein R₃, R₄ and R₅ arehydrogen; and further wherein R₂ is fluorine; and further wherein R₆ isC(O)CHCH(pyridine-3-yl).

In another embodiment, the biologically active oxazolidinones are of thestructure 1b wherein R₁ of the oxazolidione is5-amino-4-cyanooxazole-2-yl; and wherein R₂ is fluorine; and furtherwherein R₃, R₄ and R₅ are hydrogen; and still further wherein R₆ isC(O)CH₃.

In another embodiment, the biologically active oxazolidinones are of thestructure 1b wherein R₁ of the oxazolidione is4-phenylthiazole-2-yl-amino; and wherein R₂ is fluorine; and furtherwherein R₃, R₄ and R₅ are hydrogen; and still further wherein R₆ isC(O)CH₃.

A variety of methods of synthesizing biologically active oxazolidinonesare provided.

In one embodiment, methods are provided for the preparation ofoxazolidinones, such as those of the structure 1b, and comprise thesteps of: providing an iminophosphorane; mixing the iminophosphoranewith a resin that comprises carbonyl groups to form an imineintermediate; and, reducing the imine intermediate to afford a compoundattached to the resin through an amine linkage. In another embodiment,the iminophosphorane is provided from an azide that is reacted with aphosphine. In another embodiment, the iminophosphorane is provided froman amine that is reacted with a (trisubstituted)phosphine dihalide.

In another embodiment, the resin comprising carbonyl groups is of thestructure

wherein R₂₃ is hydrogen, alkyl, aryl, O-alkyl or O-aryl; R₂₄ ishydrogen, CH₃O or NO₂; R₂₅ is (CH₂)_(n)CONH, wherein n is an integerranging between 1 and about 5; and, the filled circle is a polymericsupport.

In another embodiment of structure 1c, R₂₃ is hydrogen, R₂₄ is CH₃O, R₂₅is (CH₂)₃CONH and the filled circle is Tentagel,(cross-linked)polystyrene, (cross-linked)polyethylene glycol orpolyethyleneglycol-polystyrene compositions.

Methods also are provided of synthesizing biologically activeoxazolidinone compositions from a corresponding amine. In oneembodiment, the method is for the preparation of oxazolidinones, forexample, of the structure 1b, and comprises the steps of: reacting anamine with a resin that comprises carbonyl groups to form an imineintermediate; and, reducing the imine intermediate to afford a compoundattached to the resin through an amine linkage.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is shows the structure of an oxazolidinone 1b.

FIG. 2 is a scheme showing the synthesis of a combinatorial librarycomprising oxazolidinones of structure 1b, wherein R₁ is C(O)R₇R₈.

FIG. 3 is a scheme showing the synthesis of a set of azidooxazolidinones.

FIG. 4 is a scheme showing the synthesis of a combinatorial librarycomprising oxazolidinones of structure 1b, wherein R₁ is C(O)R₇R₈, andwherein R₃, R₄ and R₅ are hydrogen; and wherein in FIG. 4, the N—Acgroup of 17, 18 and 19 also may be NCOR₁, wherein R₁ is a substituent,such as H, alkyl, heteroalkyl, aryl, or heteroaryl.

FIG. 5 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is C(O)OR₉ orC(O)R₁₀.

FIG. 6 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is SR₁₁.

FIG. 7 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is S(O)R₁₁ orS(O)₂R₁₁.

FIG. 8 is a scheme showing the synthesis of a set of thio substitutedazido oxazolidinones.

FIG. 9 is a scheme showing the synthesis of a combinatorial librarycomprising oxazolidinones of structure 1b, wherein R₁ is NR₁₂R₁₃.

FIG. 10 is a scheme showing the synthesis of a combinatorial librarycomprising oxazolidinones of structure 1b, wherein R₁ is an oxazole.

FIG. 11 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is an oxazole.

FIG. 12 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is anaminothiazole.

FIG. 13 is a scheme showing the synthesis of combinatorial librariescomprising oxazolidinones of structure 1b, wherein R₁ is CH₂NR₁₈R₁₉.

FIG. 14 is a scheme showing the synthesis of a set of acetal containingazido oxazolidinones.

FIG. 15 is a scheme showing a general synthetic method for thepreparation of oxazolidinones.

FIG. 16 is a scheme showing a general synthetic method for thepreparation of azido oxazolidinones.

FIG. 17 is a graphical depiction of a linking portion connecting anoxazolidinone to a solid support.

FIG. 18 is a scheme showing the synthesis of an oxazolidinone ofstructure 1b, wherein R₁ is NR₁₂R₁₃.

FIG. 19 is a scheme showing the synthesis of an oxazolidinone ofstructure 1b wherein R₁ is an aminothiazole.

FIG. 20 is a scheme showing the synthesis of an oxazolidinone ofstructure 1b, wherein R₁ is an oxazole.

FIG. 21 is a scheme showing the synthesis of oxazolidinones of structure1b wherein R₁ is C(O)R₁₀.

FIG. 22 is a scheme showing the synthesis of oxazolidinones of structure1b, wherein R₁ is NR₁₂R₁₃.

FIG. 23 is a scheme showing a general synthetic method for thepreparation of oxazolidinones.

FIG. 24 is a scheme showing a method of preparation ofN-[(3-phenyl-2-oxo-5-oxazolidinyl)methyl]acetamide.

FIG. 25 is a scheme showing a method of preparation ofN-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide.

FIG. 26 is a scheme showing a method of preparation for solid supportbound(S)—N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]-methyl]acetamide.

FIG. 27 is a scheme showing a method of preparation for sulfonyl, amidyland ureayl derivatives of(S)—N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]-methyl]acetamide.

FIG. 28 is a scheme showing the preparation of x-thio acetamide, α,β-unsaturated acetamide and α-amino acetamide derivatives of(S)—N-[[3-(3-fluoro-4-morpholinyl-phenyl)-2-oxo-5-oxazolidinyl]-methyl]acetamide.

FIG. 29 shows a nonlimiting group of amines that are used in thepreparation of sulfonyl, amidyl and ureayl oxazolidinone combinatoriallibraries.

FIG. 30 shows another nonlimiting group of amines that are used in thepreparation of sulfonyl, amidyl and ureayl oxazolidinone combinatoriallibraries.

FIG. 31 shows another nonlimiting group of amines that are used in thepreparation of sulfonyl, amidyl and ureayl oxazolidinone combinatoriallibraries.

FIG. 32 shows a nonlimiting group of amines that are attached to a solidsupport in a manner analogous to amine 32a in FIG. 26 and then used toconstruct sulfonamide, amide and urea oxazolidinone libraries in anmanner analogous to solid support bound amine 33a in FIG. 27.

FIG. 33 is a group of amines for use in the preparation ofoxazolidonones that was for example used to prepare combinatoriallibraries comprising oxazolidinones of structure 1b, wherein R₁ isderived from the shown amine, R₂ is fluorine, R₃ is hydrogen, R₄ ishydrogen, R₅ is hydrogen and R₆ is C(O)CH₃.

FIG. 34 is a group of amines for use in the preparation ofoxazolidinones that was for example used to prepare combinatoriallibraries comprising oxazolidinones of structure 1b, wherein R₁ isderived from the shown amine, R₂ is fluorine, R₃ is hydrogen, R₄ ishydrogen, R₅ is hydrogen and R₆ is C(O)CH₃.

FIG. 35 is a group of amines for use in the preparation ofoxazolidinones that was for example used to prepare combinatoriallibraries comprising oxazolidinones of structure 1b, wherein R₁ isderived from the shown amine, R₂ is fluorine, R₃ is hydrogen, R₄ ishydrogen, R₅ is hydrogen and R₆ is C(O)CH₃.

FIG. 36 is a group of amines for use in the preparation ofoxazolidinones that was used for example to prepare combinatoriallibraries comprising oxazolidinones of structure 1b, wherein R₁ isderived from the shown amine, R₂ is fluorine, R₃ is hydrogen, R₄ ishydrogen, R₅ is hydrogen and R₆ is C(O)CHCHC₆H₄CH(p-NOCH₃) orC(O)CHCHC₆H₄(p-OCH₃).

FIG. 37 is a group of amines for use in the preparation ofoxazolidinones that was used for example to prepare combinatoriallibraries comprising oxazolidinones of structure 1b, wherein R₁ isderived from the shown amine, R₂ is fluorine, R₃ is hydrogen, R₄ ishydrogen, R₅ is hydrogen and R₆ is C(O)CH₂SCH₃ or C(O)CHCH(3-C₅H₄N).

FIG. 38 shows a group of biologically active oxazolidinone compounds,with an MIC range of about 1.25-20 μg/ml against E. faecium.

FIG. 39 is a scheme showing the synthesis of acylamino oxazolidinonecompounds and libraries, wherein R₁ and R₂ are substituents, forexample, H, alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.

FIG. 40 is a scheme showing the synthesis of sulfonamide oxazolidinonecompounds and libraries, wherein R₁ is a substituent, for example, H,alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.

FIG. 41 is a scheme showing the synthesis of sulfide oxazolidinonecompounds and libraries, wherein R₁ is a substituent, for example, H,alkyl, heteroalkyl, aryl, heteroaryl, or alkoxy.

FIGS. 42 and 43 illustrate building blocks R₂COOH that may be used forsynthesis of acylamino oxazolidinone libraries and compounds as shown inFIG. 39, and also may be used in other syntheses such as those shown inFIG. 9.

FIGS. 44 and 45 illustrate building blocks R₂X, where X is halo, whichmay be used in the synthesis of sulfide oxazolidinone libraries andcompounds as shown in FIG. 41 and also can be used as R₁₁X in thesynthesis shown in FIG. 6.

FIG. 46 illustrates sulfonyl chloride building blocks R₂SO₂Cl that maybe used in the synthesis of sulfonamide oxazolidinone libraries andcompounds as shown in FIG. 40, and also may be used in the synthesesshown in FIG. 18.

FIG. 47 illustrates amine building blocks R₇R₈NH that may be used in thesynthesis of oxazolidinone libraries and compounds as shown in FIG. 4.

FIG. 48 shows building blocks R₂R₃NH and R₁COOH that may be used to makecompounds of formula 1k and libraries thereof.

FIG. 49 is a general scheme showing routes of synthesis of3-(heteroaryl)oxazolidinones.

FIG. 50 is another general scheme showing routes of synthesis of3-(heteroaryl)oxazolidinones.

DETAILED DESCRIPTION Definitions

As used herein, the terms and phrases have the meanings and definitionsknown in the art. Some of the more commonly used phrases are describedin more detail below.

“Combinatorial library” or “array” is an intentionally createdcollection of differing molecules which can be prepared syntheticallyand screened for biological activity in a variety of different formats(e.g., libraries of soluble molecules, libraries of molecules bound to asolid support). Typically, combinatorial libraries contain between about6 and two million compounds. In one embodiment, combinatorial librariescontain between about 48 and 1 million compounds. For example,combinatorial libraries may contain between about 96 and 250,000compounds. In another embodiment, combinatorial libraries may containabout 40 to 100 compounds.

“Alkyl” refers to a cyclic, branched or straight chain chemical groupcontaining only carbon and hydrogen, such as methyl, pentyl, andadamantyl. Alkyl groups can either be unsubstituted or substituted withone or more substituents, e.g., halogen, alkoxy, acyloxy, amino,hydroxyl, mercapto, carboxy, benzyloxy, phenyl, and benzyl. Alkyl groupscan be saturated or unsaturated (e.g., containing —C═C— or —C≡C—subunits), at one or several positions. Typically, alkyl groups willcomprise about 1 to 12 carbon atoms, for example about 1 to 10, or about1 to 8 carbon atoms.

“Heteroalkyl” refers to a cyclic, branched or straight chain chemicalgroup containing carbon, hydrogen and at least one heteroatom. Theheteroatom will be typically nitrogen, oxygen or sulfur. Heteroalkylgroups can either be unsubstituted or substituted with one or moresubstituents, e.g., halogen, alkoxy, acyloxy, amino, hydroxyl, mercapto,carboxy, benzyloxy, phenyl, benzyl. Where the heteroalkyl group containsa nitrogen atom, the nitrogen atom can be primary, secondary, tertiary,quaternary or can be in various forms such as an amide or sulfonamide.Heteroalkyl groups can contain one or more unsaturated (e.g., —C═C— or—C≡C—) subunits. Typically, heteroalkyl groups will comprise 1 to 12atoms, for example 1 to 8, or 1 to 4 carbon atoms.

“Aryl” refers to a monovalent unsaturated aromatic carbocyclic grouphaving a single ring (e.g. phenyl), multiple rings (e.g. biphenyl), ormultiple condensed rings (e.g. naphthyl or anthryl). Aryl groups can beoptionally unsubstituted or substituted with amino, hydroxyl, alkyl,heteroalkyl, alkoxy, halo, mercapto and other substituents. Typically,the aryl group is a substituted single ring compound. For example, thearyl group is a substituted phenyl ring.

“Heteroaryl” refers to a monovalent unsaturated aromatic carbocyclicgroup having a single ring (e.g., pyridyl or furyl) or multiplecondensed rings (e.g., indolizinyl or benzothienyl) and having at leastone heteroatom within the ring. The heteroatom in the ring is preferablynitrogen, oxygen or sulfur. Heteroaryl groups can be optionallyunsubstituted or substituted with amino, hydroxyl, alkyl, heteroalkyl,alkoxy, halo, mercapto and other substituents. In one embodiment, theheteroaryl group is substituted.

“Electron withdrawing group” refers to a substituent that drawselectrons to itself more than a hydrogen atom would if it occupied thesame position in a molecule. This definition according to field effectis discussed in March, “Advanced Organic Chemistry,” 3d Edition, pp.16-17, Wiley-Interscience, New York. It should be contrasted with adefinition based on resonance effects. Examples of electron withdrawinggroups include —NR₂, —COOH, —OR, —SR, —F, —COR, —Cl, —SH, —NO₂, —Br,—NH₂, —SO₂R, —I, —OH, —CN, —C≡CR₂, where R is alkyl, heteroalkyl, arylor heteroaryl.

“Chemical module” refers to a general class of molecules that can beincorporated into a combinatorial library at a discrete step in thelibrary synthesis. For example, thiols are chemical modules that can becoupled to a substrate, where the synthetic route employs a nucleophileto displace a solid support bound leaving group; isocyanates arechemical modules that can be coupled to a substrate, where the syntheticroute employs an electrophile to react with a solid support bound amine.Chemical modules can contain tens, hundreds or thousands of differentindividual members.

“Protecting group” refers to a chemical group that exhibits thefollowing characteristics: (1) reacts selectively with the desiredfunctionality in good yield to give a protected substrate that is stableto the projected reactions for which protection is desired; 2) isselectively removable from the protected substrate to yield the desiredfunctionality; and 3) is removable in good yield by reagents compatiblewith the other functional group(s) generated in such protectionreactions. Examples of protecting groups can be found in Greene et al.(1991) Protective Groups in Organic Synthesis, 2nd Ed. (John Wiley &Sons, Inc., New York).

“Biologically active oxazolidinone compounds” or “bioactiveoxazolidinone compounds” refers to an oxazolidinone compound, forexample, of structure 1b that exhibits biological activity. Forinstance, a biologically active oxazolidinone can inhibit theinteraction between an enzyme or receptor and its respectivesubstrate(s) or endogenous ligand(s), or inhibit cell growth of amicroorganism, by about at least 15% at a solution concentration of 10⁻³molar or lower (i.e., it has inhibitory activity). For example, thebiologically active oxazolidinone will inhibit such processes atsolution concentrations of about 10⁻⁴ M or lower, or 10⁻⁵ M or lower,or, e.g., of about 10⁻⁶ M or lower.

“Allylic amine” refers to a compound of the following structure:

where R₃₁, R₃₂, R₃₃, R₃₄ and R₃₅ are independently selected from thegroup consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.Where R₃₁, R₃₂, R₃₃, R₃₄ and R₃₅ are all hydrogen, the allylic amine isallylamine. “Phosgene equivalent” refers to a chemical reagent that canadd a C═O group to a molecule in either one or more than one chemicalsteps. A nonlimiting example of a phosgene equivalent that can add a C═Ogroup in one chemical step is carbonyldiimidazole (CDI). A nonlimitingexample of a phosgene equivalent that can add a C═O group in more thanone chemical step is ethyl chloroformate.

“Acyl” refers to a group —(C═O)—R, where R is a substituent such as H,aryl, heteroaryl, alkyl or heteroalkyl. Exemplary acyl groups includeformyl, acetyl, propionyl and butyryl.

“Sulfonyl” refers to a group —(SO₂)—R, where R is a substituent such asalkyl, heteroalkyl, aryl, or heteroaryl. Exemplary sulfonyl groupsinclude methylsulfonyl and trifluoromethylsulfonyl.

Oxazolidinones

Provided are oxazolidinones and combinatorial libraries thereof, as wellas methods for their synthesis, for example by solid phase synthesismethods.

In one embodiment, oxazolidinones have the following structure:

where R₁ is selected from the group consisting of alkyl, heteroalkyl,aryl and heteroaryl; R₂ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, aryl and heteroaryl; R₃ is selected fromthe group consisting of hydrogen, alkyl, heteroalkyl, aryl andheteroaryl; R₁₁ is selected from the group consisting of hydrogen,alkyl, heteroalkyl, aryl and heteroaryl; and R₁₂ is selected from thegroup consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.

In another embodiment, R₃ of the oxazolidinones 1a is selected from thegroup consisting of aryl and heteroaryl, where the aryl and heteroarylgroups are the aryl and heteroaryl groups attached to the amines ofTable 2 and FIGS. 29, 30 and 31.

In another embodiment, R₃ of the oxazolidinones 1a is a heteroaryl groupsuch as a pyridyl group, a thienylphenyl group, an oxazolyl group or apyrrolyl group, or is a (morpholino)fluorophenyl group.

In another embodiment, the oxazolidinones have the structure

where R₁ is selected from the group consisting of alkyl, heteroalkyl,aryl and heteroaryl, R₂ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, aryl and heteroaryl, and R₃ has thestructure

where ‘X’ is selected from the group consisting of hydrogen, electronwithdrawing groups, alkyl, heteroalkyl, aryl and heteroaryl, and ‘Y’ isselected from the group consisting of hydrogen, electron withdrawinggroups, alkyl, heteroalkyl, aryl and heteroaryl.

In another embodiment, R₃ of the oxazolidinones 1d is the followingstructure:

In another embodiment, R₁ of the oxazolidinones 1d is the followingstructure:

where R₁₅ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl and heteroaryl, and where R₁₆ is selected from thegroup consisting of alkyl, heteroalkyl, aryl and heteroaryl.

In one embodiment, oxazolidinones are provided that are antimicrobialcompounds. In one embodiment, the antimicrobial compounds have thestructure:

where R₃ is selected from the group consisting of aryl and heteroaryl,and where R₂₀ is selected from the group consisting of structures A, B,C, I, J and K:

where m is 0, 1, 2 or 3, and where n is 0, 1, 2 or 3, and where R₂₁ isselected from the group consisting of alkyl, heteroalkyl, aryl andheteroaryl, and where R₂₂, R₂₃ and R₂₄ are independently selected fromthe group consisting of hydrogen, alkyl, heteroalkyl and heteroaryl, andwhere R₂₅ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl and heteroaryl, and where R₃₀ is selected from thegroup consisting of alkyl, heteroalkyl, aryl and heteroaryl.

In another embodiment, R₃ of the antimicrobial compound 1e is selectedfrom the group consisting of aryl and heteroaryl, where the aryl andheteroaryl groups are the aryl and heteroaryl groups attached to theamines of Table 2 and FIGS. 29, 30 and 31.

In another embodiment, R₃ of the antimicrobial compound 1e has thefollowing structure:

where X and Z are independently selected from the group consisting ofhydrogen and fluoride, and where Y is selected from the group consistingof structures D, E, F, G and H:

where R₂₆ is selected from the group consisting of hydrogen, alkyl,heteroalkyl, aryl and heteroaryl.

In another embodiment, Y of the antimicrobial compound 1e has thestructure D:

In another embodiment, the antimicrobial compound has the structure:

where m is 0, 1, 2 or 3, and where R₂₂, R₂₃ and R₂₄ are independentlyselected from the group consisting of hydrogen, alkyl, heteroalkyl andheteroaryl.

In another embodiment, m in the antimicrobial compound 1f is 0, R₂₂ andR₂₃ are hydrogen, and R₂₄ is an aryl group.

In another embodiment, the antimicrobial compound is of the structure

where R₃₅, R₃₆ and R₃₇ are independently selected from the groupconsisting of hydrogen, an electron withdrawing group, alkyl,heteroalkyl, aryl and heteroaryl.

In another embodiment, oxazolidinones and combinatorial librariesthereof, of the structure 1b shown in FIG. 1 are provided:

In one embodiment, substituent R₁ of compound 1b is one of the followingfunctional groups: C(O)NR₇R₈, wherein R₇ and R₈ are, independently,hydrogen, alkyl, heteroalkyl, aryl or heteroaryl (See FIGS. 33, 34, 35,36 and 37 for nonlimiting examples of amines used to construct suchlibraries); C(O)OR₉, wherein R₉ is hydrogen, alkyl, heteroalkyl, aryl orheteroaryl; C(O)R₁₀, wherein R₁₀ is hydrogen, alkyl, heteroalkyl, arylor heteroaryl; SR₁₁, wherein R₁₁ is hydrogen, alkyl, heteroalkyl, arylor heteroaryl; S(O)₂R₁₁, wherein R₁₁ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; S(O)R₁₁, wherein R₁₁ is hydrogen, alkyl,heteroalkyl, aryl or heteroaryl; NR₁₂R₁₃, wherein R₁₂ and R₁₃ are,independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, aryl orheteroaryl; NR_(x)(C═O)R_(y), wherein R_(x) and R_(y) are independentlyhydrogen, alkyl, heteroalkyl, aryl, or heteroaryl; NR_(x)(SO₂)R_(y),wherein R_(x) and R_(y) are independently hydrogen, alkyl, heteroalkyl,aryl, or heteroaryl, provided R_(y) is not H; 2-oxazolyl, wherein R₁₄ isat the 4-position and R₁₅ is at the 5-position, and wherein R₁₄ and R₁₅are, independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or anelectron withdrawing group; 2-aminothiazolyl, wherein R₁₆ is at the4-position and R₁₇ is at the 5-position, and wherein R₁₆ and R₁₇ are,independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or anelectron withdrawing group; and, CH₂NR₁₈R₁₉, wherein R₁₈ and R₁₉ are,independently, hydrogen, alkyl, heteroalkyl, aryl, heteroaryl, acyl orsulfonyl. The substituents R₂, R₃, R₄ and R₅ are, independently,hydrogen, alkyl, heteroalkyl, heteroaryl or an electron withdrawinggroup; and, R₆ is acyl or sulfonyl.

In one embodiment, the substituents of compound 1b are defined asfollows: R₁ is C(O)NR₇R₈, wherein R₇ is hydrogen and R₈ is alkyl,heteroalkyl aryl or heteroaryl; R₂ is an electron withdrawing group; R₃,R₄ and R₅ are hydrogen; and R₆ is acyl. In one embodiment, thesubstituents are as follows: R₁ is C(O)NR₇R₈, wherein R₇ is hydrogen andR₈ is aryl or heteroaryl; R₂ is a halogen; R₃, R₄ and R₅ are hydrogen;and R₆ is acyl, wherein the acyl group is of the structureC(O)(CH₂)_(n)CH₃, and wherein n is an integer ranging from 0 to about 5.In one embodiment, the substituents are as follows: R₁ is C(O)NR₇R₈,wherein R₇ is hydrogen and R₈ is heteroaryl; R₂ is fluorine (F); R₃, R₄and R₅ are hydrogen; and R₆ is acyl, wherein the acyl group is of thestructure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is C(O)OR₉, wherein R₉ is alkyl, heteroalkyl, aryl orheteroaryl; R₂ is an electron withdrawing group; R₃, R₄ and R₅ arehydrogen; and R₆ is acyl. In one embodiment the substituents are asfollows: R₁ is C(O)OR₉, wherein R₉ is alkyl or heteroalkyl; R₂ is ahalogen; R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein the acylgroup is of the structure C(O)(CH₂)_(n)CH₃, and wherein n is an integerranging from 0 to about 5. For example, the substituents are as follows:R₁ is C(O)OR₉, wherein R₉ is alkyl; R₂ is fluorine; R₃, R₄ and R₅ arehydrogen; and, R₆ is acyl, wherein the acyl group is of the structureC(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is C(O)R₁₀, wherein R₁₀ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; R₂ is an electron withdrawing group; R₃, R₄ and R₅are hydrogen; and R₆ is acyl. In one embodiment, the substituents are asfollows: R₁ is C(O)R₁₀, wherein R₁₀ is alkyl or aryl; R₂ is a halogen;R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein the acyl group is ofthe structure C(O)(CH₂)_(n)CH₃, and wherein n is an integer ranging from0 to about 5. For example, the substituents are as follows: R₁ isC(O)R₁₀, wherein R₁₀ is alkyl; R₂ is fluorine; R₃, R₄ and R₅ arehydrogen; and R₆ is acyl, wherein the acyl group is of the structureC(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is SR₁₁, wherein R₁₁ is alkyl, heteroalkyl, aryl orheteroaryl; R₂ is an electron withdrawing group; R₃, R₄ and R₅ arehydrogen; and, R₆ is acyl. In one embodiment, the substituents are asfollows: R₁ is SR₁₁, wherein R₁₁ is alkyl or heteroalkyl; R₂ is ahalogen; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acylgroup is of the structure C(O)(CH₂)_(n)CH₃. For example, thesubstituents are as follows: R₁ is SR₁₁, wherein R₁₁ is alkyl; R₂ isfluorine; R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein the acylgroup is of the structure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is S(O)₂R₁₁, wherein R₁₁ is alkyl, heteroalkyl, aryl orheteroaryl; R₂ is an electron withdrawing group; R₃, R₄ and R₅ arehydrogen; and, R₆ is acyl. In one embodiment, the substituents are asfollows: R₁ is S(O)₂R₁, wherein R₁₁ is alkyl or heteroalkyl; R₂ is ahalogen; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acylgroup is of the structure C(O)(CH₂)_(n)CH₃. For example, thesubstituents are as follows: R₁ is S(O)₂R₁₁, wherein R₁₁ is alkyl; R₂ isfluorine; R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein the acylgroup is of the structure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is S(O)R₁₁, wherein R₁₁ is alkyl, heteroalkyl, aryl orheteroaryl; R₂ is an electron withdrawing group; R₃, R₄ and R₅ arehydrogen; and, R₆ is acyl. In one embodiment, the substituents are asfollows: R₁ is S(O)R₁₁, wherein R₁₁ is alkyl or heteroalkyl; R₂ is ahalogen; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acylgroup is of the structure C(O)(CH₂)_(n)CH₃. For example, thesubstituents are as follows: R₁ is S(O)R₁₁, wherein R₁₁ is alkyl; R₂ isfluorine; R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein the acylgroup is of the structure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is NR₁₂R₁₃, wherein R₁₂ is hydrogen and R₁₃ is hydrogen,alkyl, heteroalkyl, aryl, heteroaryl, acyl or sulfonyl; R₂ is anelectron withdrawing group; R₃, R₄ and R₅ are hydrogen; R₆ is acyl. Inone embodiment, the substituents are as follows: R₁ is NR₁₂R₁₃, whereinR₁₂ is hydrogen and R₁₃ is acyl or sulfonyl; R₂ is a halogen; R₃, R₄ andR₅ are hydrogen; and, R₆ is acyl, wherein the acyl group is of thestructure C(O)(CH₂)_(n)CH₃, and wherein n is an integer ranging from 0to about 5. For example, the substituents are as follows: R_(1 is NR)₁₂R₁₃, wherein R₁₂ is hydrogen and R₁₃ is acyl; R₂ is fluorine; R₃, R₄and R₅ are hydrogen; and, R₆ is acyl, wherein the acyl group is of thestructure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is 2-oxazolyl, wherein R₁₄ is at the 4-position and R₁₅ isat the 5-position, and wherein R₁₄ and R₁₅ are, independently, hydrogen,alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group;R₂ is an electron withdrawing group; R₃, R₄ and R₅ are hydrogen; and, R₆is acyl. In one embodiment, the substituents are as follows: R₁ is2-oxazolyl, wherein R₁₄ is at the 4-position and R₁₅ is at the5-position, and wherein R₁₄ and R₁₅ are, independently, an electronwithdrawing group; R₂ is a halogen; R₃, R₄ and R₅ are hydrogen; and, R₆is acyl, wherein the acyl group is of the structure C(O)(CH₂)_(n)CH₃.For example, the substituents are as follows: R₁ is 2-oxazolyl, whereinR₁₄ is at the 4-position and R₁₅ is at the 5-position, and wherein R₁₄and R₁₅ are, independently, an electron withdrawing group; R₂ isfluorine; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acylgroup is of the structure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is 2-aminothiazolyl, wherein R₁₆ is at the 4-position andR₁₇ is at the 5-position, and wherein R₁₆ and R₁₇ are, independently,hydrogen, alkyl, heteroalkyl, aryl, heteroaryl or an electronwithdrawing group; R₂ is an electron withdrawing group; R₃, R₄ and R₅are hydrogen; and, R₆ is acyl. In one embodiment, the substituents areas follows: R₁ is 2-aminothiazolyl, wherein R₁₆ is at the 4-position andR₁₇ is at the 5-position, and wherein R₁₆ and R₁₇ are, independently, anelectron withdrawing group; R₂ is a halogen; R₃, R₄ and R₅ are hydrogen;and, R₆ is acyl, wherein the acyl group is of the structureC(O)(CH₂)_(n)CH₃, and wherein n is an integer ranging from 0 to about 5.For example, the substituents are as follows: R₁ is 2-aminothiazolyl,wherein R₁₆ is at the 4-position and R₁₇ is at the 5-position, andwherein R₁₆ and R₁₇ are, independently, an electron withdrawing group;R₂ is fluorine; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein theacyl group is of the structure C(O)CH₃.

In another embodiment, the substituents of compound 1b are defined asfollows: R₁ is CH₂NR₁₈R₁₉, wherein R₁₈ is hydrogen and R₁₉ is alkyl,heteroalkyl, aryl, heteroaryl, acyl or sulfonyl; R₂ is an electronwithdrawing group; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl. In oneembodiment, the substituents are as follows: R₁ is CH₂NR₁₈R₁₉, where R₁₈is hydrogen and R₁₉ is acyl or sulfonyl; R₂ is a halogen; R₃, R₄ and R₅are hydrogen; and R₆ is acyl, wherein the acyl group is of the structureC(O)(CH₂)_(n)CH₃. For example, the substituents are as follows: R₁ isCH₂NR₁₈R₁₉, wherein R₁₈ is hydrogen and R₁₉ is acyl; R₂ is fluorine; R₃,R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acyl group is ofthe structure C(O)CH₃.

Synthesis of Combinatorial Libraries of Oxazolidinones 1b

Provided are methods for the preparation of combinatorial librariescomprising oxazolidinones, for example, of the structure 1b. (For ageneral discussion of combinatorial library synthesis, see U.S. Pat. No.5,549,974, which is hereby incorporated by reference for all purposes.)In one embodiment, the methods comprise attaching an aryl oxazolidinoneto a solid support; functionalizing the 4-position of the aryl group;and removing the oxazolidinone from the solid support.

FIG. 2 shows a method for the preparation of combinatorial librariescomprising oxazolidinones of the structure 1b, wherein R₁ is C(O)NR₇R₈.A plurality of azides 2 are converted to the correspondingiminophosphoranes upon reaction with a phosphine. The ylides are mixedwith a plurality of solid supports containing a carbonyl functionalgroup, producing a plurality of imines. The imines are reduced (e.g.,NaBH₃CN) to provide a plurality of amines 3. The ester group of 3 isdeprotected to afford a plurality of acids 4. Acylation of the amine andactivation of the acid of 4 yields a plurality of activated esters 5.The activated esters are reacted with an R₇R₈NH amine unit, providing aplurality of amides 5. The solid support bound amides 5 are removed fromthe solid support using a suitable reagent (e.g., TFA) to afford aplurality of amides 7 in solution.

The plurality of azides 2 is produced starting from a set of substitutedmethylnitrobenzenes (8, FIG. 3). The methyl group of 8 is oxidized toprovide the corresponding carboxylic acids 9. The acids are esterified,affording a set of nitro esters 10. The nitro group of 10 is reduced toyield a set of amines 11. Acylation of 11 provides a set of protectedamines 12. Amines 12 are reacted with a substituted epoxide to afford aset of amino alcohols, which are cyclized to a set of oxazolidinones 13.Displacement of the primary alcohol of 13 yields the azides 2.

FIG. 4 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein thesubstituents are defined as follows: R₁ is C(O)NR₇R₈, wherein R₇ ishydrogen and R₈ is alkyl, heteroalkyl, aryl or heteroaryl; R₂ isfluorine; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acylgroup is of the structure C(O)CH₃. A plurality of azides 14 wereconverted to the corresponding iminophosphoranes upon reaction withtriphenylphosphine. The iminophosphoranes were mixed with a plurality of5-formyldimethoxyphenoxybutyric acid resin beads (BAL resin beads,Novabiochem), producing a plurality of imines. The imines were reducedwith NaBH₃CN to provide a plurality of amines 15. The ester group of 15was deprotected using trimethylsilylchloride (TMSCI) to afford aplurality of acids (16). Acylation of the amine with Ac₂O and activationof the acid with PfpOCOCF₃ yielded a plurality of activated esters 17.The activated esters were reacted with an R₇R₈NH unit, providing aplurality of amides 18. The solid support bound amides 18 were removedfrom the solid support using TFA to afford a plurality of amides 19 insolution. FIG. 47 illustrates amine building blocks R₇R₈NH that may beused in the synthesis of oxazolidinone libraries and compounds as shownin FIG. 4.

FIG. 5 shows exemplary methods for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ iseither C(O)OR₉ or C(O)R₁₀. A plurality of solid support bound acids 4are converted into activated acids 20. To prepare an oxazolidinonelibrary, wherein R₁ is C(O)OR₉, the activated acids 20 are reacted withan R₉OH unit, providing a plurality of esters 21. The esters are removedfrom the solid support upon treatment with a suitable reagent, affordinga plurality of amides 22 in solution. To prepare an oxazolidinonelibrary, wherein R₁ is C(O)R₁₀, the activated acids 20 are reacted withan amine, providing a plurality of Weinreb amides 23. The Weinreb amidesare reacted with an organometallic unit (e.g., LiAlH4 or MeMgBr),affording a plurality of ketones 24. The ketones 24 are removed from thesolid support upon treatment with a suitable reagent, producing aplurality of ketones 25 in solution.

FIG. 6 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ isSR₁₁. A plurality of azides 26 are converted to the correspondingiminophosphoranes upon reaction with a phosphine. The iminophosphoranesare mixed with a plurality of solid supports containing a carbonylfunctional group, producing a plurality of imines. The imines arereduced to provide a plurality of amines 27. Acylation of the amine anddeprotection of the sulfide of 27 yields a plurality of thiols 28.Alkylation of 28 with an electrophile provides a plurality of sulfides29. The solid support bound sulfides 29 are removed from the solidsupport using a suitable reagent to afford a plurality of sulfides 30 insolution. Another embodiment is shown in FIG. 41. FIGS. 44 and 45illustrate building blocks R₂X, where X is halo, which may be used inthe synthesis of sulfide oxazolidinone libraries and compounds as shownin FIG. 41 and also can be used as R₁₁X in the synthesis shown in FIG.6.

FIG. 7 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ isS(O)R₁₁ or S(O)₂R₁₁. To prepare an oxazolidinone library, wherein R₁ isS(O)R₁₁, a plurality of solid support bound sulfides 29 is convertedinto a plurality of sulfoxides 31 upon oxidation. The sulfoxides areremoved from the solid support upon treatment with a suitable reagent,affording a plurality of sulfoxides 32 in solution. To prepare anoxazolidinone library, wherein R₁ is S(O)₂R₁₁, a plurality of solidsupport bound sulfides 29 is converted into a plurality of sulfones 33upon oxidation. The sulfones are removed from the solid support upontreatment with a suitable reagent, affording a plurality of sulfones 34in solution.

The plurality of azides 26 is produced starting from a set ofsubstituted anilines 35. The aniline is subjected to electrophilicaromatic substitution at the 4-position, providing a set ofisothiocyanates 36. The amine portion of 36 is protected to produce 37.The isothiocyanate group of 37 is reacted with sodium sulfide and tritylbromide to afford a set of protected sulfides 38. The protected anilineof 38 is reacted with a substituted epoxide and cyclized, yielding a setof oxazolidinones 39. Conversion of the primary alcohol of 39 to anazide produces the set of azides 26. See FIG. 8.

FIG. 9 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ isNR₁₂R₁₃. A plurality of solid support bound azides 5, which contain anactivated ester, are converted into a plurality of acyl azides 40. Theacyl azides are rearranged, providing a plurality of protected anilines41. Deprotection of 41 affords a plurality of anilines 42, which arereacted with electrophilic units R₁₂X and R₁₃X to yield a plurality ofsubstituted anilines 43. The solid support bound substituted anilines 43are removed from the solid support using a suitable reagent to afford aplurality of substituted anilines 44 in solution. Another embodiment isshown in FIG. 39, which is a scheme showing the synthesis of acylaminooxazolidinone compounds and libraries, wherein R₁ and R₂ aresubstituents, for example, H, alkyl, heteroalkyl, aryl, heteroaryl, oralkoxy. FIGS. 42 and 43 illustrate building blocks R₂COOH that may beused for synthesis of acylamino oxazolidinone libraries and compounds asshown in FIG. 39, and also may be used in other syntheses such as thoseshown in FIG. 9.

FIG. 10 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ is2-oxazolyl with a cyano group at the 4-position and an amino group atthe 5-position. A plurality of azides 2 are converted to thecorresponding iminophosphoranes upon reaction with a phosphine. Theylides are mixed with a plurality of solid supports containing acarbonyl functional group, producing a plurality of amines 3. The estergroup of 3 is deprotected to provide plurality of carboxylic acids. Theamine is acylated and the carboxylic acid activated, yielding aplurality of esters 5. Reaction of 5 with amino malonitrile affords aplurality of oxazoles 45. The solid support bound oxazoles are removedfrom the solid support using a suitable reagent to produce a pluralityof oxazoles 46 in solution.

FIG. 11 shows exemplary methods for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ iseither 2-oxazolyl containing R₁₄ at the 4-position and R₁₅ and the5-position, or 2-oxazolyl containing cyano at the 4-position and R₁₅ atthe 5-position. To prepare an oxazolidinone library, wherein R₁ is2-oxazolyl containing R₁₄ at the 4-position and R₁₅ at the 5-position, aplurality of solid support bound oxazoles 45 is reacted with a reagentcapable of converting the 4-cyano group to a different functionality(e.g. hydrolysis to acid) to provide a plurality of oxazole compounds47. The 5-amino substituent of 47 is alkylated or acylated to produce aplurality of compounds 48. The solid support bound oxazoles 48 areremoved from the solid support using a suitable reagent to afford aplurality of R₁₄, R₁₅-substituted oxazoles 49 in solution. To prepare anoxazolidinone library, wherein R₁ is 2-oxazolyl containing cyano at the4-position and R₁₅ at the 5-position, the 5-amino substituent of 45 isalkylated or acylated to produce a plurality of compounds 50. The solidsupport bound oxazoles 50 are removed from the solid support using asuitable reagent to afford a plurality of cyano, R₁₅ substitutedoxazoles 51 in solution.

FIG. 12 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ is2-aminothiazolyl containing R₁₆ at the 4-position and R₁₇ at the5-position. A plurality of anilines 42 is reacted with a protectedisothiocyanate to provide a plurality of protected thiocarbamates 52.The thiocarbamates are deprotected, producing a plurality ofthiocarbamates 53. Reaction of 53 with an a-halo ketone yields aplurality of aminothiazoles 54. The solid support bound amino thiazolesare removed from the solid support using a suitable reagent to afford aplurality of aminothiazoles 55 in solution.

FIG. 13 shows an exemplary method for the preparation of combinatoriallibraries comprising oxazolidinones of the structure 1b, wherein R₁ isCH₂NR₁₈R₁₉. A plurality of azides 56 is converted to the correspondingiminophosphoranes upon reaction with a phosphine. The iminophosphoranesare mixed with a plurality of solid supports, producing a plurality ofimines. The imines are reduced and acylated to provide a plurality ofacetals 57. The acetals are removed, yielding a plurality of aldehydes58. Reductive amination of the aldehydes affords a plurality of amines59. The solid support bound amines are removed from the solid supportusing a suitable reagent to afford a plurality of amines 60 in solution.

The plurality of azides 67 is produced starting from a set ofsubstituted methylnitrobenzenes 61 (FIG. 14). The methyl group of 61 isoxidized to provide the acetals 62. Transacetalization of 62 yields aset of dimethyl acetals 63. The nitro group of 63 is reduced, affordinga set of anilines 64, which are protected 65. The protected anilines arereacted with a substituted epoxide, and the resulting amino alcohols arecyclized to yield a set of oxazolidinones 66. The primary of alcohol of66 is displaced with azide, producing 67.

Embodiments of Biologically Active Oxazolidinone Compounds

In one embodiment, biologically active oxazolidinones, for example withantibiotic activity, are provided, for example, of the structure 1b:

In one embodiment, the substituents on 1b are as follows: Substituent R₁of compound 1b is one of the following functional groups: C(O)NR₇R₈,wherein R₇ and R₈ are, independently, hydrogen, alkyl, heteroalkyl, arylor heteroaryl; C(O)OR₉, wherein R₉ is hydrogen, alkyl, heteroalkyl, arylor heteroaryl; C(O)R₁₀, wherein R₁₀ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; SR₁₁, wherein R₁₁ is hydrogen, alkyl, heteroalkyl,aryl or heteroaryl; S(O)₂R₁₁, wherein R₁₁ is hydrogen, alkyl,heteroalkyl, aryl or heteroaryl; S(O)R₁₁, wherein R₁₁ is hydrogen,alkyl, heteroalkyl, aryl or heteroaryl; NR₁₂R₁₃, wherein R₁₂ and R₁₃are, independently, hydrogen, acyl, sulfonyl, alkyl, heteroalkyl, arylor heteroaryl; 2-oxazolyl, wherein R₁₄ is at the 4-position and R₁₅ isat the 5-position, and wherein R₁₄ and R₁₅ are, independently, hydrogen,alkyl, heteroalkyl, aryl, heteroaryl or an electron withdrawing group;2-aminothiazolyl, wherein R₁₆ is at the 4-position and R₁₇ is at the5-position, and wherein R₁₆ and R₁₇ are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl or an electron withdrawing group; andCH₂NR₁₈R₁₉, wherein R₁₈ and R₁₉ are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl, acyl or sulfonyl. The substituents R₂,R₃, R₄ and R₅ are, independently, hydrogen, alkyl, heteroalkyl,heteroaryl or an electron withdrawing group; and, R₆ is acyl orsulfonyl.

In one embodiment, the biologically active oxazolidinones of structure1b are substituted as follows: R₁ is C(O)NR₇R₈, wherein R₇ is hydrogenand R₈ is alkyl, heteroalkyl, aryl or heteroaryl; R₂ is fluorine; R₃, R₄and R₅ are hydrogen; and, R₆ is acyl, wherein the acyl group is of thestructure C(O)CH₃. In one embodiment, the oxazolidinone is substitutedas follows: R₁ is C(O)NR₇R₈, wherein R₇ is hydrogen and R₈ is aryl orheteroaryl; R₂ is fluorine; R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl,wherein the acyl group is of the structure C(O)CH₃. In anotherembodiment, the oxazolidinone is substituted as follows: R₁ isC(O)NR₇R₈, wherein R₇ is hydrogen and R₈ is heteroaryl; R₂ is fluorine;R₃, R₄ and R₅ are hydrogen; and, R₆ is acyl, wherein the acyl group isof the structure C(O)CH₃.

In another embodiment, the biologically active oxazolidinones ofstructure 1b are substituted as follows: R₁ is 2-oxazolyl, containing acyano group at the 4-position and an amino group at the 5-position ofthe oxazole; R₂ and R₄ are, independently, hydrogen or an electronwithdrawing group; R₃ and R₅ are hydrogen; and, R₆ is acyl or sulfonyl.The oxazolidinone is, for example, substituted as follows: R₁ is2-oxazolyl, containing a cyano group at the 4-position and an aminogroup at the 5-position of the oxazole; R₂ is a halogen; R₃, R₄ and R₅are hydrogen; and, R₆ is acyl. In another embodiment, the oxazolidinoneis substituted as follows: R₁ is 2-oxazolyl, containing a cyano group atthe 4-position and an amino group at the 5-position of the oxazole; R₂is fluorine; R₃, R₄ and R₅ are hydrogen; and R₆ is acyl, wherein theacyl group is of the structure C(O)CH₃.

In another embodiment, the biologically active oxazolidinones ofstructure 1b are substituted as follows: R₁ is 2-aminothiazolyl, whereinthe 4-position of the thiazole contains R₁₆ and the 5-position containsR₁₇, and wherein R₁₆ and R₁₇ are, independently, hydrogen, alkyl, arylor heteroaryl; R₂ and R₄ are, independently, hydrogen or an electronwithdrawing group; R₃ and R₅ are hydrogen; and, R₆ is acyl. For example,the oxazolidinone is substituted as follows: R₁ is 2-aminothiazolyl,wherein the 4-position of the thiazole contains R₁₆ and the 5-positioncontains R₁₇, and wherein R₁₆ and R₁₇ are, independently, hydrogen,alkyl or aryl; R₂ is a halogen; R₃, R₄ and R₅ are hydrogen; and, R₆ isacyl, wherein the acyl group is of the structure C(O)CH₃. In anotherembodiment, the oxazolidinone is substituted as follows: R₁ is2-aminothiazolyl, wherein the 4-position of the thiazole contains R₁₆and the 5-position contains R₁₇, and wherein R₁₆ and R₁₇ are,independently, hydrogen or aryl; R₂ is fluorine; R₃, R₄ and R₅ arehydrogen; and, R₆ is acyl, wherein the acyl group is of the structureC(O)CH₃.

Synthesis of Biologically Active Oxazolidinone Compounds 1b

Exemplary methods for the solid phase synthesis of biologically activeoxazolidinones, for example, of the structure 1b are provided. Themethods comprise: providing an iminophosphorane; mixing theiminophosphorane with a resin that comprises carbonyl groups to form animine intermediate; and reducing the imine intermediate to afford acompound attached to the resin through an amine linkage.

FIG. 15 generally shows the solid phase synthesis of oxazolidinonecompounds. Oxazolidinone 68, wherein R₂₀ is (4-R₁)-aryl (1), isconverted into imine 71 by 1 of 2 pathways: azide 68 is treated with aphosphine (R₂₁ is alkyl or aryl) to provide iminophosphorane 69, whichis reacted with a carbonyl containing resin; or, azide 68 is reduced toamine 70, which is reacted with a carbonyl containing resin. Imine 71 isreduced using an appropriate reducing agent (e.g., NaBH₃CN), affordingcompound 72, which is attached to the resin through an amine linkage.

FIG. 16 generally shows the synthesis of compound 68. Epoxide 73 issubjected to nucleophilic attack by R₂₀NH₂, producing an amino alcohol.The amino alcohol is cyclized to provide oxazolidinone 74. Removal ofthe ester protecting group of 74 affords a primary alcohol 75.Displacement of the primary alcohol with azide yields 68.

The carbonyl containing resin is graphically depicted on FIG. 15.Substituent R₂₃ is hydrogen, alkyl, aryl, O-alkyl or O-aryl. Thepolymeric support (filled circle) is composed of a variety of materials,including, without limitation, Tentagel, (cross-linked)polystyrene,(cross-linked)polyethyleneglycol, poly-ethyleneglycol-polystyrenecompositions, and polyacrylate. Substituent R₂₂ is shown on FIG. 17: R₂₄is hydrogen, CH₃O, NO₂; and, R₂₅ is (CH₂)_(n)CONH, wherein n is aninteger ranging from 1 to about 5.

FIG. 18 shows an embodiment of the solid phase synthesis methods. Azide14 is converted into an iminophosphorane upon treatment withtriphenylphosphine. The iminophosphorane is reacted with BAL resin toprovide an imine, which is reduced with NaBH₃CN, affording amine 15.Compound 15 is reacted with TMSCl to remove the ester group (16). Theamine of 16 is acylated and the carboxylic acid is transformed into anactivated ester (17). Treatment of the activated ester with Bu₄NN₃ orTMSN₃ affords acyl azide 77. Acyl azide 77 is rearranged, yielding aprotected aniline (78). The Fmoc protecting group is removed (79), andthe resulting aniline is sulfonated with p-O₂NC₆H₄SO₂Cl (80). Thesulfonated aniline (80) is removed from the solid support upon reactionwith TFA, providing 81. Another embodiment is shown in FIG. 40. FIG. 46illustrates sulfonyl chloride building blocks R₂SO₂Cl that may be usedin the synthesis of sulfonamide oxazolidinone libraries and compounds asshown in FIG. 40, and also may be used in the syntheses shown in FIG.18.

FIG. 19 shows another embodiment of the solid phase synthesis methods.Aniline 79 is reacted with Fmoc-N═C═S to provide protected thiourea 82.The protected thiourea is treated with piperidine, affording adeprotected thiocarbamate (83). Reaction of 83 with 2-bromoacetophenoneyields thiazole 84. Treatment of 84 with TFA cleaves the thiazole fromthe solid support, providing 85.

FIG. 20 shows another embodiment of the solid phase synthesis methods.Azide 4 is converted into an iminophosphorane upon treatment withtriphenyl phosphine. The iminophosphorane is reacted with BAL resin,providing an imine. The imine is reduced using NaBH₃CN to afford solidsupport bound amine 15. The ester of 15 is deprotected using TMSCl,yielding a carboxylic acid; the amine is acylated upon reaction withAc₂O; and, the acid is activated using PfpOCOCF3, yielding 17. Reactionof 17 with aminomalonitrile provides oxazole 86. Treatment of 86 withTFA cleaves the oxazole from the solid support to afford 87.

FIG. 21 shows two embodiments of the solid phase synthesis methods.Compound 17 is treated with HN(OCH₃)CH₃ to provide Weinreb amide 88.Amide 88 is either reduced with LiAlH4 to afford aldehyde 89 or reactedwith MeMgI, a Grignard reagent, to yield ketone 91. Treatment of eitheraldehyde 89 or ketone 91 with TFA provides, respectively, cleavedproducts 90 and 92.

FIG. 22 shows two embodiments of the solid phase synthesis methods.Compound 79 is treated with either a dialdehyde to provide morpholine 93or a diacetal to afford pyrrole 95. Treatment of either morpholine 93 orpyrrole 95 with TFA provides, respectively, cleaved products 94 and 96.

FIG. 48, shows building blocks R₂R₃NH and R₁COOH that may be used tomake exemplary oxazolidinone compounds of formula 1k and librariesthereof.

Synthesis of Oxazolidinone Compounds 1a

Oxazolidinone compounds 1a and precursors thereof may be made by avariety of methods as disclosed herein.

An embodiment of a solid phase synthesis method to make amino alcohols,where R₁ is an alkyl, is shown in FIG. 23. An olefin group is attachedto the surface of a solid support (5a) providing the functionalizedresin 6a. The olefin can have the following functionality: “m” is 0, 1,or 2; “n” is 0, 1, or 2; R₁₀, R₁₁ R₁₂, R₂ and R₃ are independentlyhydrogen, alkyl, heteroalkyl, aryl or heteroaryl. The olefin ischemically modified yielding epoxide 7a. Addition of a substituted amineto the distal carbon of immobilized epoxide 7a affords solid supportbound amino alcohol 8a. Solid support bound amino alcohol 8a is treatedwith a phosgene equivalent providing oxazolidinone 15a, which is cleavedunder standard conditions to yield free oxazolidinone 16a. Acylation of16a yields oxazolidinone 16b.

Another embodiment of the solid phase synthesis method to makeoxazolidinones is shown in FIG. 24. Immobilized epoxide 12a was treatedwith aniline in the presence of lithium triflate to provide solidsupport bound amino alcohol 19a. Reaction of 19a with CDI yieldedoxazolidinone 20a. Alternatively, 20a was prepared directly from epoxide12a upon treatment with a lithium salt of aniline benzylcarbamate.Addition of TFA to oxazolidinone 20a provided free oxazolidinone 21a,which was acetylated to yield acetamide 22a.

Another embodiment of the solid phase synthesis method to makeoxazolidinones is shown in FIG. 25. PNP Wang Resin (23a) was reactedwith allyl amine to provide carbamate 24a. The terminal olefin ofcarbamate 24a was oxidized with mCPBA to yield immobilized epoxide 12a.Addition of 3-fluoro-4-morpholino aniline to 12a produced amino alcohol25a, which was cyclized to oxazolidinone 26a upon treatment with CDI.Reaction of 26a with TFA provided free amine 27a. Addition of acetylchloride to 27a produced acetamide 28a.

Synthesis of Combinatorial Libraries Comprising Oxazolidinones 1a

In one embodiment, provided are methods for the synthesis ofcombinatorial libraries comprising oxazolidinones 1a and compositionsformed from this method. In one embodiment, oxazolidinones 1a arecompounds of the following structure:

where R₁ is selected from the group consisting of alkyl, heteroalkyl,aryl and heteroaryl; R₂ is selected from the group consisting ofhydrogen, alkyl, heteroalkyl, aryl and heteroaryl; R₃ is selected fromthe group consisting of hydrogen, alkyl, heteroalkyl, aryl andheteroaryl; R₁₁ is selected from the group consisting of hydrogen,alkyl, heteroalkyl, aryl and heteroaryl; and R₁₂ is selected from thegroup consisting of hydrogen, alkyl, heteroalkyl, aryl and heteroaryl.

An embodiment of the solid phase method to make oxazolidinone libraries,where R₁ is an alkyl group, is described in reference to FIG. 23. Olefingroups are attached to the surface of a plurality of solid supports 5aproviding functionalized resins 6a. The olefin groups can have thefollowing functionality: “m” is 0, 1, or 2; “n” is 0, 1, or 2; R₂, R₃,R₁₀, R₁₁ and R₁₂ are independently hydrogen, alkyl, heteroalkyl, aryl orheteroaryl. The individual olefin groups are chemically modified toyield epoxides 7a. Addition of different amine units to the distalcarbon of the epoxides 7a affords a plurality of amino alcohols 8a.

A plurality of solid support bound amino alcohols 8a is treated with aphosgene equivalent to provide a plurality of oxazolidinones 15a, whichare cleaved under standard conditions to yield the free oxazolidinones16a.

Another embodiment of the solid phase method to make oxazolidinonelibraries is shown in FIGS. 26 and 27. Carboxylic acid 30a is attachedto amine resin 29a to provide amide 31a. Reductive amination of 31aemploying amine 32a yields the functionalized amine 33a, which is addedto an array of individual reaction chambers. Addition of sulfonylchloride units to a plurality of amines 33a produces the sulfonamides34a. The sulfonamides are cleaved from the solid support using standardconditions providing a plurality of free sulfonamides 35a. Addition ofcarboxylic acid or carboxylic acid derivative units to a plurality ofamines 33a produces the amides 36a. The amides 36a are cleaved from thesolid support using standard conditions providing a plurality of freeamides 37a. Addition of isocyanate units to a plurality of amines 33aproduces the ureas 38a. The ureas 38a are cleaved from the solid supportusing standard conditions providing a plurality of free ureas 39a.

Another embodiment of the solid phase method to make oxazolidinonelibraries is shown in FIG. 28. Coupling of α-bromo acetic acid to amine33a provides amide 40a, which is divided into an array of individualreaction chambers. Nucleophilic addition of thiol units to a pluralityof amides 40a yields the α-thio amides 41a, which are cleaved from thesolid support upon treatment with TFA producing a plurality of freeα-thio amides 42a. Nucleophilic addition of triphenylphospine to aplurality of amides 40a yields solid support bound Wittig reagents thatare coupled with aldehyde units affording a plurality of α,β-unsaturated amides 43a. The amides were cleaved from the solid supportupon treatment with TFA to produce a plurality of free α, β-unsaturatedamides 44a. Nucleophilic addition of amine units to a plurality ofamides 40a yields the α-amino amides 45a, which are cleaved from thesolid support upon treatment with TFA producing a plurality of freeα-amino amides 46a.

3-(Polysubstituted)oxazolidinones

A variety of 3-(polysubstituted)oxazolidinones are provided, whichoptionally have biological activity, such as antimicrobial activity.

In one embodiment, 3-(polysubstituted)oxazolidinones 2c as well ascombinatorial libraries comprising the compounds are provided:

In 2c, in one embodiment:

-   -   R₆ is acyl or sulfonyl;    -   R₇ is aryl or heteroaryl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O,        OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or (CH₂)_(n)O, where        n=1-6, and R and R′ are substituents, for example, independently        H, or alkyl, such as C₁-C₇ alkyl, or heteroalkyl, aryl or        heteroaryl; and    -   R₉ is hydrogen, OH, alkyl, aryl, heteroalkyl, or heteroaryl.

In another embodiment,3-[4-(heteroaryl)aminocarbonylaryl]-oxazolidinones and 3-[4-(N-oxideheteroaryl)aminocarbonylaryl]-oxazolidinones are provided.

In one embodiment of 2c:

-   -   R₆ is C(═O)R, where R is a substituent, for example, H or alkyl,        such as C₁-C₇ alkyl, such as methyl or ethyl, or, e.g.,        heteroalkyl, aryl or heteroaryl;    -   R₇ is aryl;    -   R₈ is an amide group, such as NH(C═O) or NR′(C═O), where R′ is a        substituent, for example, H, heteroalkyl, aryl, heteroaryl, or        alkyl, such as C₁-C₇ alkyl, such as methyl; and    -   R₉ is hydrogen or a heteroaryl group, such as an unsubstituted        or substituted heteroaryl group, wherein the heteroaryl group is        for example pyridinyl, thiazolyl, benzothiazolyl, isothiazolyl,        quinolinyl, 1,3,4-triazolyl, or 1,3,4-thiadiazolyl.

For example, compounds of formula 2d are provided:

wherein

-   -   R₉ is hydrogen or an unsubstituted or substituted heteroaryl        group, such as pyridinyl, thiazolyl, benzothiazolyl,        isothiazolyl, quinolinyl, 1,3,4-triazolyl, or        1,3,4-thiadiazolyl; and    -   R and R′ are substituents, for example, independently H or        alkyl, such as C₁-C₇ alkyl, such as methyl, or, e.g.,        heteroalkyl, aryl or heteroaryl.

Exemplary compounds are shown below.

In one embodiment the following nine preferred compounds are provided,which have an MIC against S. aureus of about 0.5 to 1 μg/mL using astandard whole cell assay as disclosed herein.

The following nine compounds also are provided that have an MIC againstS. aureus of about 2 to 4 μg/mL using a standard whole cell assay asdisclosed herein.

Also provided are the following compounds.

Other exemplary oxazolidinone compounds within the scope of theinvention are shown below:

Further provided are 3-(aminocarbonyl)oxazolidinones of formula 2c,wherein:

-   -   R₆ is an acyl group, such as C(═O)R, where R is a substituent,        for example, H or alkyl, such as C₁-C₇ alkyl, including methyl,        or e.g., heteroalkyl, aryl or heteroaryl;    -   R₇ is aryl;    -   R₈ is NH(C═O); and    -   R₉ is hydrogen or OH;

Exemplary compounds are shown below:

In one embodiment the following compound is provided, which has an MICagainst S. aureus of about 0.5 μg/mL using a standard whole cell assayas disclosed herein.

3-[(Substituted)aryl]oxazolidinones

A variety of 3-[(substituted)aryl]oxazolidinones are provided, whichoptionally are biologically active, for example as antimicrobialcompounds.

In one embodiment oxazolidinones of formula 3c, and combinatoriallibraries comprising compounds of formula 3c are provided:

In one embodiment in 3c:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, NRC(═O), C(═O), C(═O)O,        OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or (CH₂)_(n)O, where        n=0-6, and where R and R′ are substituents, for example,        independently H or alkyl, such as C₁-C₇ alkyl, or, e.g.,        heteroalkyl, aryl or heteroaryl; and    -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl.

In a further embodiment, 3-[4-(alkylthio)aryl]oxazolidinones areprovided. For example, compounds of formula 3c are provided, wherein:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is acyl, such as C(═O)CH₃;    -   R₇ is an aryl group;    -   R₈ is thio group, such as S; and    -   R₉ is a heteroalkyl group.

In another embodiment, compounds of formula 3d are provided:

wherein

-   -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl; and    -   R′ is a substituent, for example, H or alkyl, such as C₁-C₇        alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

Exemplary compounds are shown below.

In one preferred embodiment, the following three compounds are providedthat have an MIC against S. aureus of about 2 μg/mL using a standardwhole cell assay as disclosed herein.

In another embodiment, the following four compounds are provided thathave an MIC against S. aureus of about 8 μg/mL using a standard wholecell assay as disclosed herein.

Also provided are the following compounds:

In another embodiment, 3-[4-(ester group)aryl]oxazolidinones useful asantimicrobial agents are provided. For example, compounds of formula 3care provided wherein:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is an acyl group, such as C(═O)CH₃;    -   R₈ is an ester, such as OC(═O); and    -   R₉ is an alkyl group, such as a C₁-C₇ alkyl group.

In one embodiment, compounds of structure 3e are provided:

wherein

-   -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl; and    -   R′ is a substituent, for example, H or alkyl, such as C₁-C₇        alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

Exemplary compounds are shown below:

3-[(Substituted)heteroaryl]oxazolidinones

In another embodiment, a variety of3-[(substituted)heteroaryl]oxazolidinones, which optionally arebiologically active, for example, as antimicrobial compounds, areprovided.

In one embodiment, compounds of the formula 4c, and combinatoriallibraries thereof are provided:

In one embodiment of 4c:

-   -   R₆ is acyl or sulfonyl;    -   Het₁ is heterocyclic group such as an unsubstituted or        substituted heteroaryl group, such as thienylphenyl, thiazolyl,        1,3,4-thiadiazolyl, pyridinyl, or pyrimidinyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O), C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and R and R′ are substituents, for        example, independently, H, or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl; and    -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl.

In 4c, substituents on the heteroaryl group Het₁ are, for example,independently, hydrogen, alkyl, aryl, heteroalkyl, electron withdrawinggroup, F, Cl, CN, NO₂, NR″R′″, OH, OR″, SR″, S(═O)R″, SO₂R″, C(═O)R″,C(═O)OR″, OC(═O)R″, C(═O)NR″R′″, N(R″)C(═O)R′″, or N-oxide group in theHet₁ nuclei, and R″ and R′″ are substituents, for example areindependently H or alkyl, such as C₁-C₇ alkyl, or, e.g., heteroalkyl,aryl or heteroaryl.

3-[4-(Linked heteroaryl)aryl]oxazolidinones

In a further embodiment, 3-[4-(linked heteroaryl)aryl]oxazolidinones areprovided, which optionally have biological activity, for example, asantimicrobial compounds.

For example, compounds of the formula 5c, and combinatorial librariesthereof are provided:

In one embodiment of 5c:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, NRC(═O), C(═O)NOR C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and R and R′ are substituents, for        example, independently H or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl; and    -   Het₂ is a heterocyclic group, such as an unsubstituted or        substituted heterocyclic group, such as an oxazolyl, isoxazolyl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl,        thienylphenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,        1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-triazinyl,        1,2,4-triazinyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,        pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, or        1,2,4,5-tetrazinyl;    -   wherein substituents in heteroaryl group Het₂ are, for example,        independently, hydrogen, alkyl, aryl, heteroalkyl, electron        withdrawing group, F, Cl, CN, NO₂, NR″R′″, OH, OR″, SR″,        S(═O)R″, SO₂R″, C(═O)R″, C(═O)OR″, OC(═O)R″, C(═O)NR″R′″,        N(R″)C(═O)R′″, or N-oxide group in the Het₂ nuclei, where R″ and        R′″ are substituents, for example, independently H or alkyl,        such as C₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

In another embodiment, 3-[4-(linked heteroaryl)aryl]oxazolidinones areprovided, which optionally have antimicrobial activity, of formula 5cwherein:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is acyl, for example, C(═O)CH₃;    -   R₇ is an aryl group;    -   R₈ is a thio group, such as S; and    -   Het₂ is a substituted or unsubstituted thienylphenyl or        thiazolyl heteroaryl group.

Also provided are compounds of structure 5d:

wherein

-   -   Het₂ is a substituted or unsubstituted thienylphenyl or        thiazolyl heteroaryl group; and    -   R′ is a substituent, for example, H or alkyl, such as C₁-C₇        alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

Exemplary compounds are shown below:

In another embodiment, 3-[4-(triazinylamino)aryl] oxazolidinones areprovided, which are optionally antimicrobial compounds. For example,compounds of formula 5c are provided wherein:

-   -   R₂, R₃, R₄ and R₅ are, independently, hydrogen, alkyl,        heteroalkyl, heteroaryl or an electron withdrawing group;    -   R₆ is acyl, such as C(═O)CH₃;    -   R₈ is amino group, such as NH; and    -   Het₂ is 1,3,5-triazinyl.

Additionally, compounds of structure 5e are provided:

wherein

-   -   Het₂ is a unsubstituted or substituted 1,3,5-triazinyl; and    -   R′ is a substituent, for example, H or alkyl, such as C₁-C₇        alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

Exemplary compounds are shown below:

3-[4-(Linked heteroaryl)heteroaryl]oxazolidinones

In another embodiment, 3-[4-(linked heteroaryl)heteroaryl]oxazolidinonesare provided, which are optionally biologically active, for example, asantimicrobial compounds.

For example, compounds of formula 6c, and combinatorial librariesthereof are provided:

In one embodiment of 6c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, NRC(═O), C(═O)NOR C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and R and R′ are substituents, for        example, independently H or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl;    -   Het₁ is a heterocyclic group such as an unsubstituted or        substituted heterocyclic group, for example, thienylphenyl,        thiazolyl, 1,3,4-thiadiazolyl, pyridinyl, pyrimidinyl, phenyl or        fluorophenyl;    -   wherein substituents in heteroaryl group Het₁ are independently,        for example, hydrogen, alkyl, aryl, heteroalkyl, electron        withdrawing group, F, Cl, CN, NO₂, NR″R′″, OR″, SR″, S(═O)R″,        SO₂R″, C(═O)R″, C(═O)OR″, OC(═O)R″, C(═O)NR″R′″, N(R″)C(═O)R′″,        or N-oxide group in the Het₁ nuclei, where R″ and R′″ are        substituents, for example, independently H or alkyl, such as        C₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or heteroaryl; and    -   Het₂ is an unsubstituted or substituted heterocyclic preferably        heteroaryl group, such as an oxazolyl, isoxazolyl,        1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3-oxadiazolyl,        thienylphenyl, thiazolyl, isothiazolyl, 1,2,3-thiadiazolyl,        1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, pyrrolyl, imidazolyl,        pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-triazinyl,        1,2,4-triazinyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl,        pyridazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl, or        1,2,4,5-tetrazinyl;    -   wherein substituents in heteroaryl group Het₂ are independently,        for example, hydrogen, alkyl, aryl, heteroalkyl, electron        withdrawing group, F, Cl, CN, NO₂, NR_(x)R_(y), OH, OR_(x),        SR_(x), S(═O)R_(x), SO₂R_(x), C(═O)R_(x), C(═O)OR_(x),        OC(═O)R_(x), C(═O)NR_(x)R_(y), N(R_(x))C(═O)R_(y), or N-oxide        group in the Het₂ nuclei, where R_(x) and R_(y) are        substituents, for example, independently H or alkyl, such as        C₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

3-(Substituted pyridyl)oxazolidinones

Also provided are 3-(substituted pyridyl)oxazolidinones, which areoptionally biologically active, for example as antimicrobial compounds.

In one embodiment, compounds of the formulas 7c or 8c and combinatoriallibraries thereof are provided:

In one embodiment, in 7c and 8c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O), C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, wherein n=0-6, and wherein R and R′ are        substituents, for example, independently H or alkyl, such as        C₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or heteroaryl;    -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl; and    -   R₁₀, R₁₁ and R₁₂ are, for example, independently hydrogen,        alkyl, aryl, heteroalkyl, electron withdrawing group, F, Cl, CN,        NO₂, NR″R′″, OR″, SR″, S(═O)R″, SO₂R″, C(═O)R″, C(═O)OR″,        OC(═O)R″, C(═O)NR″R′″, N(R″)C(═O)R₉′″, or N-oxide group in the        pyridine nuclei, where R″ and R′″ are substituents, for example,        independently H or alkyl, such as C₁-C₇ alkyl, or, e.g.,        heteroalkyl, aryl or heteroaryl.

3-(Substituted pyrimidinyl)oxazolidinones

A variety of 3-(substituted pyrimidinyl)oxazolidinones, which optionallyhave biological activity, such as antimicrobial activity, also areprovided. In one embodiment, compounds of the formulas 9c and 10c, aswell as combinatorial libraries thereof, are provided:

In one embodiment of 9c and 10c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl group, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O),        C(═O), C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and where R and R′ are substituents,        for example, independently H or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl;    -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl; and

R₁₀ and R₁₁ are independently hydrogen, alkyl, aryl, heteroalkyl,electron withdrawing group, F, Cl, CN, NO₂, NR″R′″, OR″, SR″, S(═O)R″,SO₂R″, C(═O)R″, C(═O)OR″, OC(═O)R″, C(═O)NR″R′″, N(R″)C(═O)R′″, orN-oxide group in the pyrimidine nuclei, where R″ and R′″ aresubstituents, for example, independently H or alkyl, such as C₁-C₇alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

3-(Thienyl)oxazolidinones

A variety of 3-(thienyl)oxazolidinones are provided, which optionallyhave biological activity, such as antimicrobial activity.

In one embodiment, compounds of formulas 11c, 12c and 13c, andcombinatorial libraries thereof are provided:

In one embodiment of formulas 11c, 12c and 13c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O), C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and where R and R′ are substituents,        for example, independently H or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl;    -   R₉ is an alkyl, aryl, heteroalkyl, or heteroaryl group; and

R₁₀ and R₁₁ are independently hydrogen, alkyl, aryl, heteroalkyl,electron withdrawing group, F, Cl, CN, NO₂, NR″R′″, OR″, SR″, S(═O)R″,SO₂R″, C(═O)R″, C(═O)OR″, OC(═O)R″, C(═O)NR″R′″, N(R″)C(═O)R′″, where R″and R′″ are substituents, for example, independently H or alkyl, such asC₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or heteroaryl.

3-(Thiazolyl)oxazolidinones

Also provided are 3-(thiazolyl)oxazolidinones, which optionally havebiological activity, such as antimicrobial activity.

In one embodiment, compounds of formulas 14c, 15c and 16c, andcombinatorial libraries thereof are provided:

In one embodiment of 14c, 15c and 16c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O), C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, wherein n=0-6, and wherein R and R′ are        substituents, for example, independently H or alkyl, such as        C1-C7 alkyl, or, e.g., heteroalkyl, aryl or heteroaryl;    -   R₉ is an alkyl, aryl, heteroalkyl, or heteroaryl group; and    -   R₁₀ is hydrogen, alkyl, aryl, heteroalkyl, electron withdrawing        group, F, Cl, CN, NO₂, NR″R′″, OR″, SR″, S(═O)R″, SO₂R″,        C(═O)R″, C(═O)OR″, OC(═O)R″, C(═O)NR″R′″, or N(R″)C(═O)R′″,        where R″ and R′″ are substituents, for example, independently H        or alkyl, such as C₁-C₇ alkyl, or, e.g., heteroalkyl, aryl or        heteroaryl.

3-(1,3,4-Thiadiazolyl)oxazolidinones

A variety of 3-(1,3,4-thiadiazolyl)oxazolidinones are provided, whichoptionally have biological activity, such as antimicrobial activity.

In one embodiment, compounds of formula 17c and combinatorial librariesthereof are provided:

In one embodiment of 17c:

-   -   R₆ is acyl or sulfonyl;    -   R₈ is C₁-C₇ alkyl, NR, O, S, C(═O)NR, C(═O)NOR, NRC(═O), C(═O),        C(═O)O, OC(═O), S(═O), SO₂, SO₂NR, NRSO₂, NRCONR′, or        (CH₂)_(n)O, where n=0-6, and where R and R′ are substituents,        for example, independently H or alkyl, such as C₁-C₇ alkyl, or,        e.g., heteroalkyl, aryl or heteroaryl; and    -   R₉ is alkyl, aryl, heteroalkyl, or heteroaryl.

Synthesis of 3-(Heteroaryl)Oxazolidinones

3-(Heteroaryl)oxazolidinones and other oxazolidinones may be synthesizedby a variety of routes as disclosed herein. In one embodiment, thesynthesis may be conducted as shown in FIG. 49, wherein the synthesisincludes: reaction of an appropriate heteroaryl halide with3-aminopropane-1,2-diol; cyclization of the resulting(heteroaryl)aminodiol with phosgene or equivalent; conversion of5-(R)-hydroxymethyl-3-heteroaryloxazolidinone into resin immobilized5-(S)-aminomethyl-3-heteroaryl oxazolidinone. Further reaction of thisreagent produces the desired oxazolidinone.

In another embodiment, which is illustrated in FIG. 50, the5-(S)-azidomethyl-3-heteroaryloxazolidinone reagent is produced from anappropriate heteroarylhalide and 5-(S)-azidomethyloxazolidinone orequivalent thereof in the presence of a base. The resulting azide oramine intermediate is then immobiilzed on a BAL linker resin. Furtherreaction of the X group and or the amine group attached to the solidphase provides an array of desired 3-heteroaryloxazolidones.

As will be appreciated by those skilled in the art, using these andother methods disclosed herein, based on the teachings of thespecification, the oxazolidinones disclosed herein can be readilysynthesized.

Combinatorial Library Synthesis

Combinatorial library synthesis is typically performed on a solidsupport. See, for example, Lam et al. (1991) Nature 354:82-84; andHoughten et al. (1991) Nature 354:84-86. There are two generaltechnologies for the construction of combinatorial libraries: “mix andsplit” technology and “multiple parallel synthesis” technology.

For the “mix and split” technology, a large number of beads or particlesare suspended in a suitable carrier (such as a solvent) in a parentcontainer. The beads, for example, are provided with a functionalizedpoint of attachment for a chemical module. The beads are then dividedand placed in various separate reaction vessels. The first chemicalmodule is attached to the bead, providing a variety of differentlysubstituted solid supports. Where the first chemical module includes 3different members, the resulting substituted beads can be represented asA₁, A₂ and A₃.

The beads are washed to remove excess reagents and subsequently remixedin the parent container. This bead mixture is again divided and placedinto various separate reaction vessels. The second chemical module iscoupled to the first chemical module. Where the second chemical moduleincludes 3 different members, B₁, B₂ and B₃, 9 differently substitutedbeads result: A₁B₁, A₁B₂, A₁B₃, A₂B₁, A₂B₂, A₂B₃, A₃B₁, A₃B₂ and A₃B₃.Each bead will have only a single type of molecule attached to itssurface.

The remixing/redivision synthetic process can be repeated until each ofthe different chemical modules has been incorporated into the moleculeattached to the solid support. Through this method, large numbers ofindividual compounds can be rapidly and efficiently synthesized. Forinstance, where there are 4 different chemical modules, and where eachchemical module contains 20 members, 160,000 beads of differentmolecular substitution can be produced.

Combinatorial library synthesis using the “mix and split” technology canbe performed either manually or through the use of an automated process.For the manual construction of a combinatorial library, a scientistwould perform the various chemical manipulations. For the constructionof a combinatorial library through an automated process, the variouschemical manipulations will typically be performed robotically. Forexample, see U.S. Pat. No. 5,463,564.

For the “multiple parallel synthesis” technology, beads or particles aresuspended in a suitable carrier (such as a solvent) in an array ofreaction chambers. The beads or particles are provided with afunctionalized point of attachment for a chemical module. Differentmembers of a chemical module are added to each individual reactionchamber, providing an array of differently functionalized beads. Wherethere are 96 separate reaction chambers and 96 different chemical modulemembers, a combinatorial library of 96 compounds is formed. Thecompounds can be assayed on the solid support, cleaved from the solidsupport and then assayed, or subjected to the addition of anotherchemical module.

Combinatorial library synthesis using the “multiple parallel synthesis”technology can be performed either manually or through the use of anautomated process. For the manual construction of a combinatoriallibrary, a scientist would perform the various chemical manipulations.For the construction of a combinatorial library through an automatedprocess, the various chemical manipulations will typically be performedrobotic ally.

Solid Supports

The solid phase synthesis of the compositions provided herein in oneembodiment is performed on a solid support. “Solid support” includes aninsoluble substrate that has been appropriately derivatized such that achemical module can be attached to the surface of the substrate throughstandard chemical methods. Solid supports include, but are not limitedto, beads and particles such as peptide synthesis resins. For example,see Merrifield (1963) J. Am. Chem. Soc. 85:2149-2154; U.S. Pat. No.4,631,211; and Geysen et al. (1984) Proc. Natl. Acad. Sci. USA81:3998-4002.

Solid supports can consist of many materials, limited primarily by thecapacity of the material to be functionalized through synthetic methods.Examples of such materials include, but are not limited to, polymers,plastics, resins, polysaccharides, silicon or silica based materials,carbon, metals, inorganic glasses and membranes. Preferred resinsinclude Sasrin resin (a polystyrene resin available from BachemBioscience, Switzerland), Wang resin or p-nitrophenylcarbonate Wangresin (PNP resin, Novabiochem), and TentaGel S AC, TentaGel PHB, orTentaGel S NH₂ resin (polystyrene-polyethylene glycol copolymer resinsavailable from Rapp Polymere, Tubingen, Germany or from Perseptive,Boston).

The solid support can be purchased with suitable functionality alreadypresent such that a chemical module can be attached to the supportsurface (e.g., Novabiochem, Bachem Bioscience, Rapp Polymere).Alternatively, the solid support can be chemically modified such that achemical module can be attached to the support surface. Grant (1992)Synthetic Peptides. A User's Guide, W.H. Freeman and Co.; and Hermkenset al. (1996) Tetrahedron 52:4527-4554. One of ordinary skill in the artwill understand that the choice of functionality used for attaching amolecule to the solid support will depend on the nature of the compoundto be synthesized and the type of solid support. Examples offunctionality present on the solid support that can be used to attach achemical module include, but are not limited to, alkyl or aryl halides,aldehydes, alcohols, carbonates, ketones, amines, sulfides, carboxylgroups, aldehyde groups and sulfonyl groups.

The functional group on the solid support that permits the attachment ofa chemical module is, for example, an alcohol, an amine, an aldehyde, acarbonate, or a diol group. Gordon et al. (1994) J. Med. Chem.37:1385-1401; and Hermkens et al. (1996) Tetrahedron 52:4527-4554.

For making certain combinatorial libraries, one can purchase a solidsupport with an existing, protected chemical module already attached. Anexample of such a support is FmocGly Sasrin, which is commerciallyavailable from Bachem. Typically, however, the first step of thecombinatorial library synthesis is the attachment of a chemical moduleto the solid support through the existing functionality on the supportsurface. Examples of chemical reactions that can be used to attach achemical module to the support include, but are not limited to,nucleophilic displacement of a halide or other leaving group,etherification of an alcohol, esterification of an alcohol, amidation ofan amine, carbamation of an amine, reductive amination of a carbonylcompound, acetalization of an aldehyde and ketalization of a ketone.Hermkens et al. (1996) Tetrahedron 52:4527-4554.

The reaction used to attach the chemical module to the solid support is,for example, a carbamation of an amine, a reductive amination of acarbonyl compound or a nucleophilic displacement of a halide or otherleaving group. For example, see Hermkens et al. (1996).

For the attachment of certain chemical modules to the solid support, itmay be necessary to mask functionality that is not involved in theattachment process, but that is incompatible with the mode ofattachment. A non-limiting example of this type of process is theesterification of an alcohol functionalized solid support, using ahydroxyl-substituted carboxylic acid as the coupling partner. Prior tothe esterification reaction, the hydroxyl group of the carboxylic acidwould be “protected” through alkylation, silylation, acetylation, orthrough another method known to one of skill in the art. Strategies forthe use of masking or protecting groups have been well-described in theart, such as in Green (1985) Protecting Groups in Organic Synthesis,Wiley.

Methods of Compound Cleavage from a Solid Support

The cleavage of oxazolidinones from a solid support to produce thecorresponding “free” compounds can be accomplished using a variety ofmethods. For example, a compound can be photolytically cleaved from asolid support (Wang et al. (1976) J. Org. Chem. 41:3258; Rich et al.(1975) J. Am. Chem. Soc. 97:1575-1579), and through nucleophilic attack(U.S. Pat. No. 5,549,974), or through hydrolysis (Hutchins et al. (1994)Tetrahedron Lett. 35:4055-4058). The cleavage of compounds from a solidsupport to produce soluble compounds is accomplished, for example, usinghydrolytic conditions, such as through the addition of trifluoroaceticacid.

Screening

The libraries of this invention can be used to select one or morebioactive molecules. Preferably, the bioactive molecules possessactivity against a cellular target, including but not limited to enzymesand receptors, or a microorganism. A target cellular ligand ormicroorganism is one that is known or believed to be of importance inthe etiology or progression of a disease. Examples of disease states forwhich amino alcohol, thio alcohol, oxazolidinone and sulfone librariescan be screened include, but are not limited to, inflammation,infection, hypertension, central nervous system disorders, andcardiovascular disorders.

Several methods have been developed in recent years to screen librariesof compounds to identify bioactive molecules. Methods for isolatinglibrary compound species that demonstrate desirable affinity for areceptor or enzyme are well-known in the art.

For example, an enzyme solution can be mixed with a solution of thecompounds of a particular combinatorial library under conditionsfavorable to enzyme-ligand binding. See Bush et al. (1993) AntimicrobialAgents and Chemotherapy 37:851-858; and Daub et al. (1989) Biochemistry27:3701-3708. Specific binding of library compounds to the enzyme can bedetected, for instance, by any of the numerous enzyme inhibition assayswhich are well known in the art. Compounds which are bound to the enzymeare separated readily from compounds which remain free in solution byapplying the solution to a suitable separation material such as SephadexG-25 gel filtration column. Free enzyme and enzyme-ligand complexes passthrough the column quickly, while free library compounds are retarded intheir progress through the column. The mixture of enzyme-ligand complexand free enzyme is then treated with a suitable denaturing agent, suchas guanidinium hydrochloride or urea, to cause release of the ligandfrom the enzyme. The solution is then injected onto an HPLC column (forexample, a Vydac C-4 reverse-phase column, and eluted with a gradient ofwater and acetonitrile ranging from 0% acetonitrile to 80%acetonitrile). Diode array detection provides discrimination of thecompounds of the combinatorial library from the enzyme. The compoundpeaks are then collected and subjected to mass spectrometry foridentification.

An alternate manner of identifying compounds that inhibit an enzyme isto divide the library into separate sublibraries where one step in thesynthesis is unique to each sublibrary. To generate a combinatoriallibrary, reactants are mixed together during a step to generate a widemixture of compounds. At a certain step in the synthesis, however, theresin bearing the synthetic intermediates is divided into severalportions, with each portion then undergoing a unique transformation. Theresin portions are then (separately) subjected to the rest of thesynthetic steps in the combinatorial synthetic method. Each individualresin portion thus constitutes a separate sublibrary. When testing thecompounds, if a given sublibrary shows more activity than the othersublibraries, the unique step of that sublibrary is then held fixed. Thesublibrary then becomes the new library, with that step fixed, and formsthe basis for another round of sublibrary synthesis, where a differentstep in the synthesis is optimized. This procedure is executed at eachstep until a final compound is arrived at. The aforementioned method isthe generalization of the method described in Geysen, WO 86/00991, fordetermining peptide “mimotopes,″to the synthetic method of thisinvention.

Finding a compound that inhibits an enzyme is performed most readilywith free compound in solution. The compounds can also be screened whilestill bound to the resin used for synthesis; in some applications, thismay be the preferable mode of finding compounds with the desiredcharacteristics. For example, if a compound that binds to a specificantibody is desired, the resin-bound library of compounds is contactedwith an antibody solution under conditions favoring a stableantibody-compound-resin complex. A fluorescently labeled second antibodythat binds to the constant region of the first antibody is thencontacted with the antibody-compound-resin complex. This allowsidentification of a specific bead as carrying the compound recognized bythe first antibody binding site. The bead is then physically removedfrom the resin mixture and subjected to mass spectral analysis. If thesynthesis is conducted in a manner such that only one compound is likelyto be synthesized on a particular bead, then the binding compound hasbeen identified. If the synthesis is carried out so that many compoundsare present on a single bead, the information derived from analysis canbe utilized to narrow the synthetic choices for the next round ofsynthesis and identification.

The enzyme, antibody, or receptor target need not be in solution.Antibody or enzyme can be immobilized on a column. The library ofcompounds is then passed over the column, resulting in the retention ofstrongly binding compounds on the column after weaker-binding andnon-binding compounds are washed away. The column is then washed underconditions that dissociate protein-ligand binding, which removes thecompounds retained in the initial step. These compounds are thenanalyzed, and synthesized separately in quantity for further testing.Similarly, cells bearing surface receptors are contacted with a solutionof library compounds. The cells bearing bound compounds are readilyseparated from the solution containing non-binding compounds. The cellsare then washed with a solution which dissociates the bound ligand fromthe cell surface receptor. Again, the cells are separated from thesolution, and the solution analyzed.

Pharmaceutical Compositions

The present invention also provides pharmaceutical compositions whichcomprise a bioactive oxazolidinone compound or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. Thecompositions of the invention include those in a form adapted for oral,topical or parenteral use and can be used for the treatment of bacterialinfection in mammals including humans.

The antibiotic compounds, also referred to herein as antimicrobialcompounds, according to the invention can be formulated foradministration in any convenient way for use in human or veterinarymedicine, by analogy with other antibiotics. Such methods are known inthe art and are not described in detail herein.

The composition can be formulated for administration by any route knownin the art, such as subdermal, by-inhalation, oral, topical orparenteral. The compositions may be in any form known in the art,including but not limited to tablets, capsules, powders, granules,lozenges, creams or liquid preparations, such as oral or sterileparenteral solutions or suspensions.

The topical formulations of the present invention can be presented as,for instance, ointments, creams or lotions, eye ointments and eye or eardrops, impregnated dressings and aerosols, and may contain appropriateconventional additives such as preservatives, solvents to assist drugpenetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, suchas cream or ointment bases and ethanol or oleyl alcohol for lotions.Such carriers may be present, for example, from about 1% up to about 98%of the formulation. For example, they may form up to about 80% of theformulation.

Tablets and capsules for oral administration may be in unit dosepresentation form, and may contain conventional excipients such asbinding agents, for example syrup, acacia, gelatin, sorbitol,tragacanth, or polyvinylpyrollidone; fillers, for example lactose,sugar, maize-starch, calcium phosphate, sorbitol or glycine; tablettinglubricants, for example magnesium stearate, talc, polyethylene glycol orsilica; disintegrants, for example potato starch; or acceptable wettingagents such as sodium lauryl sulphate. The tablets may be coatedaccording to methods will known in normal pharmaceutical practice.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for reconstitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives, such as suspending agents, for example sorbitol,methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats, emulsifying agents, for example lecithin, sorbitan monooleate, oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, oily esters such as glycerine, propylene glycol, orethyl alcohol; preservatives, for example methyl or propylp-hydroxybenzoate or sorbic acid, and, if desired, conventionalflavoring or coloring agents.

For parenteral administration, fluid unit dosage forms are preparedutilizing the compound and a sterile vehicle, water being preferred. Thecompound, depending on the vehicle and concentration used, can be eithersuspended or dissolved in the vehicle or other suitable solvent. Inpreparing solutions, the compound can be dissolved in water forinjection and filter sterilized before filling into a suitable vial orampoule and sealing. Advantageously, agents such as a local anestheticpreservative and buffering agents can be dissolved in the vehicle. Toenhance the stability, the composition can be frozen after filling intothe vial and the water removed under vacuum. The dry lyophilized powderis then sealed in the vial and an accompanying vial of water forinjection may be supplied to reconstitute the liquid prior to use.Parenteral suspensions are prepared in substantially the same mannerexcept that the compound is suspended in the vehicle instead of beingdissolved and sterilization cannot be accomplished by filtration. Thecompound can be sterilized by exposure to ethylene oxide beforesuspending in the sterile vehicle. Advantageously, a surfactant orwetting agent is included in the composition to facilitate uniformdistribution of the compound.

The compositions may contain, for example, from about 0.1% by weight,e.g., from about 10-60% by weight, of the active material, depending onthe method of administration. Where the compositions comprise dosageunits, each unit will contain, for example, from about 50-500 mg of theactive ingredient. The dosage as employed for adult human treatment willrange, for example, from about 100 to 3000 mg per day, for instance 1500mg per day depending on the route and frequency of administration. Sucha dosage corresponds to about 1.5 to 50 mg/kg per day. Suitably thedosage is, for example, from about 5 to 20 mg/kg per day.

Pharmaceutical Applications

The oxazolidinones disclosed herein can be used in a variety ofpharmaceutical applications.

The compounds may be used, for example, as pharmaceutically activeagents that act on the peripheral nerves, adrenergic receptors,cholinergic receptors, the skeletal muscles, the cardiovascular system,smooth muscles, the blood circulatory system, synoptic sites,neuroeffector junctional sites, endocrine and hormone systems, theimmunological system, the reproductive system, the skeletal system,autocoid systems, the alimentary and excretory systems, the histaminesystem and central nervous systems as well as other biological systems.Thus, the compounds may be used as sedatives, psychic energizers,tranquilizers, anticonvulsants, muscle relaxants, anti-Parkinson agents,analgesics, antiinflammatories, local anesthetics, muscle contractants,antibiotic, antiviral, antiretroviral, antimalarials, diuretics, lipidregulating agents, antiandrogenic agents, antiparasitics, neoplastics,antineoplastics and chemotherapy agents. These compounds could furtherbe used to treat cardiovascular diseases, central nervous systemdiseases, cancer, metabolic disorders, infections and dermatologicaldiseases as well as other biological disorders and infections. Thecompounds also may be used as monoamine oxidase inhibitors.

In one embodiment, the compounds may be used as antimicrobial agents forthe treatment of infectious disorders that are caused by microbialagents, such as bacteria.

In one embodiment, compositions, for treating or preventing infectiousdisorders are provided, comprising an oxazolidone compound as disclosedherein in combination with a pharmaceutically acceptable carrier.

In another embodiment, there is provided a dosage amount of anoxazolidinone as disclosed herein in an effective amount for thetreatment, prevention or alleviation of a disorder, such as aninfectious disorder.

Oxazolidinones can be screened for activity against different microbialagents and appropriate dosages may be determined using methods availablein the art. Advantageously, the methods of making combinatoriallibraries as disclosed herein permit large quantities of oxazolidinonesto be made and screened against a wide variety of microbial agents topermit the rapid isolation of an effective oxazolidinone for aparticular target microbe. The method also may be used to determine newoxazolidinones for use after and if bacterial resistance occurs.

The compounds may be used to treat a subject to treat, prevent, orreduce the severity of an infection. Subjects include animals, plants,blood products, cultures and surfaces such as those of medical orresearch equipment, such as glass, needles and tubing.

In one embodiment, methods of treating or preventing an infectiousdisorder in a subject, such as a human or other animal subject, areprovided, by administering an effective amount of an oxazolidinone asdisclosed herein to the subject. In one embodiment, the compound isadministered in a pharmaceutically acceptable form optionally in apharmaceutically acceptable carrier. As used herein, an “infectiousdisorder” is any disorder characterized by the presence of a microbialinfection, such as bacterial infections. Such infectious disordersinclude, for example central nervous system infections, external earinfections, infections of the middle ear, such as acute otitis media,infections of the cranial sinuses, eye infections, infections of theoral cavity, such as infections of the teeth, gums and mucosa, upperrespiratory tract infections, lower respiratory tract infections,genitourinary infections, gastrointestinal infections, gynecologicalinfections, septicemia, bone and joint infections, skin and skinstructure infections, bacterial endocarditis, burns, antibacterialprophylaxis of surgery, and antibacterial prophylaxis inimmunosuppressed patients, such as patients receiving cancerchemotherapy, or organ transplant patients. The compounds andcompositions comprising the compounds can be administered by routes suchas topically, locally or systemically. Systemic application includes anymethod of introducing the compound into the tissues of the body, e.g.,intrathecal, epidural, intramuscular, transdermal, intravenous,intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The specific dosage of antimicrobial to be administered,as well as the duration of treatment, may be adjusted as needed.

The compounds of the invention may be used for the treatment orprevention of infectious disorders caused by a variety of bacterialorganisms. Examples include Gram positive and Gram negative aerobic andanaerobic bacteria, including Staphylococci, for example S. aureus;Enterococci, for example E. faecalis; Streptococci, for example S.pneumoniae; Haemophilus, for example H. influenza; Moraxella, forexample M. catarrhalis; and Escherichia, for example E. coli. Otherexamples include Mycobacteria, for example M. tuberculosis;intercellular microbes, for example Chlamydia and Rickettsiae; andMycoplasma, for example M. pneumoniae.

The following examples are provided to illustrate but not limit theclaimed invention.

EXAMPLES

Abbreviations: ACN, acetonitrile; CDI, carbonyldiimidazole; DIEA,diethylisopropylamine; DCM, dichloromethane; DIC, diisopropyldiimide;DMF, dimethylformamide; HATU, O-(7-azabenzotriazol-1-yl)-1,1,3,3-bis(tetramethylene)-uronium hexafluorophosphate; NMM, N-methylmorpholine; mCPBA, m-chloro-peroxybenzoic acid; TFA, trifluoroaceticacid; THF, tetrahydrofuran; TMOF, trimethylorthoformate.

General. Reagents were obtained from Aldrich (St. Louis, Mo.), Sigma(St. Louis, Mo.), Bachem Biosciences, Rapp Polymere, Perseptive, andNovabiochem, and used without further purification. The resin Tentagel SNTi was purchased from Rapp Polymere. Concentration of solutions afterworkup was performed by reduced pressure rotary evaporation, or usingthe Savant's SpeedVac instrument. Reactions with moisture-sensitivereagents were performed under nitrogen atmosphere.

Mass-spectra were obtained using ESI technique. HTLC analysis andpurification were performed using Beckman System Gold R®; detection at220 nm. Analytical EPLC was performed on YMC 5 micron C18 (4.6 mm×50 mm)reverse phase column (gradient from 100% of the aq. 0.1% TFA to 100% of0.1% TFA in MECN over 6 min′, flow rate 2.0 mL/min). Preparative TLC wasperformed using EM silica gel 60 F₂₅₄ plates (20×20 cm, thickness 2min).

NMR spectra were obtained on a Varian Gemini 300 MHz instrument withCDCl₃ as solvent, unless otherwise noted. 1H NMR spectra were reportedas follows: chemical shift relative to tetramethylsilane (0.00 ppm),multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet,b=broad), coupling, and integration.

2-Fluoro-4-Nitrobenzoic Acid

Concentrated sulfuric acid (32 ml) was added carefully with stirring toa solution of 2-fluoro-4-nitrotoluene (16.5 g, 0.106 mol) in acetic acid(200 ml). The mixture was warmed up to 95° C., and solution of chromiumtrioxide (37.1 g, 0.371 mol) in water (32 ml) was added dropwise withstirring over 2 h. The mixture was heated with stirring for another 30minutes, allowed to cool down to r.t., and poured into water (1000 ml).The product was extracted with diethyl ether (3×200 ml). Combined etherlayers were washed with water and evaporated to dryness. The residue wasdissolved in 10% aqueous potassium carbonate and washed with ether. Theaqueous layer was acidified with con. HCl, and the resulting whiteprecipitate filtered and dried (16.3 g, 83%), m.p. 174-177° C. ¹H NMR.

Tert-Butyl 2-Fluoro-4-Nitrobenzoate

Thionyl chloride (45 ml, 0.62 mol) was added to 2-fluoro-4-nitrobenzoicacid (23.0 g, 0.124 mol), and the mixture was stirred under reflux for 2h. Solvent was removed under vacuum, and the residue thoroughly driedunder vacuum to give crystalline acid chloride (25.2 g, 99%). The acidchloride was dissolved in tetrahydrofuran (150 ml) under nitrogen, and1M lithium tert-butoxide in tetrahydrofuran (136 ml, 0.136 mol) wasadded dropwise with stirring at room temperature. The mixture wasstirred overnight, diluted with water (300 ml) and extracted with ether.The ether layer was washed with saturated aqueous sodium bicarbonate,brine, and dried (MgSO₄). Solvent was removed under vacuum to gave theproduct as a white crystalline solid (24.2 g, 81%); mp 81-82° C. ¹H NMR.

tert-Butyl-2-Fluoro-4-Aminobenzoate

Tert-butyl 2-fluoro-4-nitrobenzoate (24.2 g, 0.100 mol) was added to awarm (95° C.) solution of ammonium chloride (53.5 g, 1.00 mol),dissolved in ethanol (300 ml) and water (150 ml). Iron powder (325 mesh,16.8 g, 0.300 mol) was added with stirring in small portions over ca. 1h. The reaction mixture was stirred and heated at 95° C. for another 30minutes and then filtered while still warm. The filter cake was washedthoroughly with excess ethanol. The filtrate and washings were dilutedwith water (1 L) and extracted with ether (3×150 ml).

Combined ether extracts were washed with water and brine, dried (MgSO₄),and evaporated to give the product as an off-white solid (21.1 g, 98%);mp 100-101° C. ¹H NMR.

O-Benzyl-N-(3-fluoro-4-butoxycarbonylphenyl)carbamate

Benzyl chloroformate (15.9 ml, 0.112 mol) was added dropwise withstirring to a mixture of tert-butyl-2-fluoro-4-aminobenzoate (21.5 g,0.102 mol) and pyridine (16.5 ml, 0.204 mol) in dichloromethane (200 ml)at 0° C. The reaction mixture was stirred for 30 minutes at 0° C.,allowed to warm up to room temperature, and then poured into water (ca.300 ml). The organic layer was separated, washed with water, brine anddried (MgSO₄). Evaporation gave a white solid, which was washed withhexane and dried under vacuum to afford the product (32.8 g, 93%); mp117-118° C. ¹H NMR.

5-(R)-Hydroxymethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

1M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (104 ml, 0.104mol) was added dropwise with stirring at −78° C. to a solution ofO-benzyl-N-(3-fluoro-4-butoxycarbonylphenyl)-carbamate (32.8 g, 0.0948mol) in tetrahydrofuran (150 ml). The mixture was stirred at −78° C. for1 hour, and then (R)-glycidyl butyrate (15.0 g, 0.104 mol) was addeddropwise with stirring. The mixture was allowed to warm to roomtemperature overnight, and was then quenched with saturated aqueousammonium chloride (100 ml). The mixture was extracted with ethylacetate, and the combined organic layers washed with water, brine, anddried (MgSO₄). Solvent was removed under vacuum, and the crude productpurified by silica gel column chromatography (eluent: 30% ethyl acetatein hexanes) to afford the product as a white solid (20.0 g, 68%); mp148-149° C. ¹H NMR.

5-(S)-Azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

Methanesulfonyl chloride (2.61 ml, 0.0337 mol) was added dropwise withstirring to a solution of5-(R)-hydroxymethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(10.0 g, 0.0321 mol) and triethylamine (6.71 ml, 0.0482 mol) indichloromethane (150 ml) at 0° C. over ca. 15 minutes. The reactionmixture was allowed to warm up to room temperature and then poured intowater. The organic layer was separated, washed with water, saturated aq.NaHCO₃, brine, and dried (MgSO₄). Solvent was removed under vacuum toafford the mesylate intermediate as an oil (11.6 g, 99%). A mixture ofthe mesylate (13.4 g, 0.0370 mol) and sodium azide (12.0 g, 0.185 mol)in DMF (130 ml) was heated with stirring at 75° C. for 12 h. Thereaction mixture was cooled to room temperature, diluted with water (300ml), and extracted with ethyl acetate (3×100 ml). Combined organiclayers were washed with water and brine, dried (MgSO₄) and evaporated.The residue was washed with diethyl ether to give the pure azide as awhite solid (9.76 g, 90.5%); mp 91-92° C. ¹H NMR.

S-(S)-Azidomethyl-3-[4′-N-methyl-N-methoxyamido-3′-fluorophenyl]oxazolidine-2-one

5-(S)-Azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(3.36 g, 0.01 mol) is dissolved in dichloromethane (ca. 100 ml), andtrifluoroacetic acid (50 ml) added with stirring. The mixture is kept atroom temperature for 3-4 h, solvent removed under vacuum, and residuewashed with diethyl ether-hexanes (1: 3, ca. 20 ml) to afford anintermediate acid. The acid (1.40 g, 0.005 mol) is dissolved indichloromethane (100 ml) and dimethylformamide (50 ml), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g,0.005 mol) added. The mixture is stirred for ca. 2 h, andN-methyl-N-methoxyamine hydrochloride (0.48 g, 0.005 mmol) added,followed by triethylamine (1.5 ml, 0.015 mmol). The mixture is stirredat room temperature for 3-4 h, poured into water (ca. 200 ml), andextracted with ethyl acetate (3×150 ml). Combined organic layers arewashed with water (4×250 ml), brine, and dried (MgSO₄). Solvent isremoved under vacuum to afford the Weinreb amide.

2-Fluoro-4-nitrobenzylidene diacetate

2-Fluoro-4-nitrotoluene (21.65 g, 0.140 mol) was dissolved in aceticanhydride (145 ml) and concentrated sulfuric acid (30 ml) was addedslowly with stirring. The mixture was cooled to 0° C., and a solution ofchromium trioxide (42.0 g, 0.420 mol) in acetic anhydride (200 ml) addedat such a rate that the temperature did not exceed 10° C. The reactionmixture was stirred at 0° C. for another 2 h, and then poured into icewater (1000 ml). The resulting precipitate was filtered, washed withwater and then dissolved in ethyl acetate. The ethyl acetate solutionwas washed with saturated aq. sodium bicarbonate, brine, and dried(MgSO₄). Solvent was removed under vacuum to afford the product as awhite crystalline solid (37.9 g, 70 %); mp 116-117° C. ¹H NMR.

2-Fluoro-4-nitrobenzaldehyde Dimethyl Acetal

2-Fluoro-4-nitrobenzylidene diacetate (9.30 g, 0.0343 mol) was dissolvedin methanol (200 ml), and potassium carbonate (4.74 g, 0.0343 mol) wasadded in one portion. The mixture was stirred at room temperature for 2h and then evaporated to dryness. The residue was dissolved in diethylether, washed with water, brine, and dried (MgSO₄). Solvent was removedunder vacuum to afford an aldehyde intermediate (5.68 g, 98 %) Thealdehyde (6.00 g, 0.0355 mol) was dissolved in a mixture of methanol(4.5 ml) and trimethyl orthoformate (4.27 ml,. 0.0390 mol). Ammoniumchloride (0.10 g, 0.00178 mol) was added, and the mixture was refluxedfor 2 h. Solvent was removed under vacuum, and the residue was washedwith diethyl ether. The resulting ether solution was washed with water,brine, and dried (MgSO₄). Solvent was removed under vacuum to afford theproduct as a colorless oil. Yield 7.60 g (99 %). ¹H NMR.

4-Amino-3-fluorobenzaldehyde Dimethyl Acetal

2-Fluoro-4-nitrobenzaldehyde dimethyl acetal (0.59 g, 2.74 mmol) wasdissolved in methanol: (20 ml), and 5% palladium on carbon (0.059 g) wasadded. The flask was charged with hydrogen gas, and the mixture wasstirred at room temperature for 20 h. The catalyst was filtered throughCelite, and solvent was removed under vacuum to afford the product.Yield 0.40 g (78 %). ¹H NMR.

O-Benzyl-N-[3-fluoro-4-(dimethoxymethyl)phenyl]carbamate

Benzyl chloroformate (0.34 ml, 2.38 mmol) was added dropwise withstirring to a solution of 4-amino-3-fluorobenzaldehyde dimethyl acetal(0.40 g, 2.16 mmol) and pyridine (0.26 ml, 3.24 mmol) in dichloromethane(10 ml) at 0° C. The reaction mixture was allowed to warm to roomtemperature, and was washed with water, brine, and dried (MgSO₄).Solvent was removed under vacuum to give the desired product as a whitesolid. Yield 0.56 g (81%). ¹H NMR.

S—(R)-Hydroxymethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]oxazolidine-2-one

1 M Lithium bis(trimethylsflyl)amide in tetrahydrofuran (0.86 ml, 0.941mmol) was added dropwise with stirring at −78° C. toO-benzyl-N-[3-fluoro-4-(dimethoxymethyl)-phenyl]carbamate (0.273 g,0.855 mmol) in tetrahydrofuran (5 ml). The mixture was stirred at −78°C. for 1 h, and then (R)-glycidyl butyrate (0.145 ml, 1.03 mmol) wasadded dropwise with stirring. The mixture was allowed to warm to roomtemperature overnight, and was then quenched with saturated aq. ammoniumchloride (5 ml). The mixture was extracted with ethyl acetate, and theproduct was washed with water, brine, and dried (MgSO₄). Solvent wasremoved in vacuum, and the crude product purified by silica gel columnchromatography (eluent: 30 % ethyl acetate in hexanes) to give thealcohol as an oil. Yield 0.24 g, 99%. ¹H NMR.

5-(S)-Azidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]oxazolidine-2-one

Methanesulfonyl chloride (0.0664 ml, 0.858 mmol) was added with stirringto a solution ofS—(R)-hydroxymethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]oxazolidine-2-one(0.233 g, 0.817 mmol) and triethylamine (0.228 ml, 1.63 mmol) indichloromethane (10 ml) at 0° C. The reaction was allowed to warm toroom temperature, and was then poured into water. The organic layer wasseparated and washed with water, saturated aq. NaHCO₃, brine, and dried(MgSO₄). Solvent was removed under vacuum to give a mesylateintermediate as an oil (0.246 g, 83%). A mixture of the mesylate (0.189g, 0.520 mmol) and sodium azide (0.170 g, 2.60 mmol) in DMF (5 ml) washeated at 75° C. for 12 h. The reaction was cooled to room temperature,diluted with water (50 ml) and extracted with ethyl acetate (3×30 ml).The combined organic layers were washed with water, brine, and thendried (MgSO₄). Solvent was removed in vacuum, and the crude product waspurified by silica gel column chromatography (eluent: 50% ethyl acetatein hexanes) to give the desired product as a colorless oil (0.154 g,95%). MS (m/z): 311 [M+H]⁺. ¹H NMR.

3-Fluoro-4-thiocyanoaniline

N-Bromosuccinimide (1.76 g, 9.89 mmol) and potassium thiocyanate (1.75g, 18.0 mmol) in methanol (30 ml) were stirred for 15 minutes at roomtemperature. The reaction mixture was cooled to 0° C., and3-fluoroaniline (1.00 g, 9.0 mmol) was added dropwise. The mixture wasstirred at 0° C. for 2 h. Solvent was removed under vacuum, and theresidue was washed with dichloromethane. The mixture was filtered toremove succinimide by-product, and the solution was washed with water,brine, and dried (MgSO₄). Solvent was removed under vacuum to afford thedesired product as a colorless oil. Yield 1.45 g (96%). ¹H NMR.

O-Benzyl-N-[3-fluoro-4-(thiocyano)phenyl]carbamate

Benzyl chloroformate (1.87 ml, 13.1 mmol) was added to a mixture of3-fluoro-4-thiocyanoaniline (2.00 g, 11.9 mmol) and pyridine (2.12 ml,26.2 mmol) in dichloromethane (30 ml) at 0° C. The mixture was stirredfor 30 minutes at 0° C., allowed to warm to room temperature, and thenpoured into water. The organic layer was separated, washed with brine,and dried (MgSO₄). Solvent was removed under vacuum. The crude productwas washed with ether-hexanes and dried under vacuum to afford thedesired product. Yield 3.64 g (92%); m.p. 74-75° C. ¹H NMR.

O-Benzyl-N-[3-fluoro-4-(triphenylmethylthio)phenyl]carbamate

Sodium sulfide nonahydrate (0.794 g, 3.31 mmol) in water (3 ml) wasadded dropwise at room temperature to a solution ofO-benzyl-N-[3-fluoro-4-(thiocyano)phenyl]carbamate (1.00 g, 3.31 mmol)in ethanol (10 ml). The reaction mixture was stirred at room temperaturefor 30 minutes, and then triphenylmethyl bromide (1.07 g, 3.31 mol) in1,4-dioxane (5 ml) was added dropwise. The reaction was stirredovernight. Organic solvent was removed under vacuum, and the residuetaken up in ethyl acetate. The solution was washed with water, brine,and dried (MgSO₄). Solvent was removed under vacuum, and the crudeproduct purified by silica gel column chromatography (eluent: 10% ethylacetate in hexanes) to give the desired compound as a white solid. Yield1.10 g, (64%); mp 152-153 -C. ¹H NMR.

5-(R)-Hydroxymethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

1M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (54 mL, 69.9mmol) was added dropwise with stirring at −78° C. to a solution ofO-benzyl-N-[3-fluoro-4-(triphenylmethylthio)phenyl]carbamate (33.0 g,63.5 mmol) in tetrahydrofuran (250 ml). The mixture was stirred at −78°C. for 1 hour, and then (R)-glycidyl butyrate (11.0 g, 76.2 mmol) wasadded dropwise with stirring. The mixture was allowed to warm up to roomtemperature overnight, and then quenched with saturated aqueous ammoniumchloride (125 ml). The mixture was extracted with ethyl acetate, andcombined organic layers washed with water, brine, and dried (MgSO₄).Solvent was removed under vacuum, and the crude product purified bysilica gel column chromatography (gradient from 30% to 75% of ethylacetate in hexane) to afford the product. TLC: R_(f) 0.2 (ethylacetate-hexanes 1:1). MS 486 [M+H]⁺. ¹H NMR.

5-(S)-Azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

Methanesulfonyl chloride (3.91 mL, 50.6 mmol) was added dropwise withstirring to a solution of5-(R)-hydroxymethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(23.4 g, 48.2 mmol) and triethylamine (10.1 mL, 73.8 mmol) indichloromethane (200 mL) at 0° C. over ca. 10 minutes. The reactionmixture was allowed to warm up to room temperature and then poured intowater. The organic layer was separated, washed with water, saturated aq.NaHCO₃, brine, and dried (MgSO₄). Solvent is removed under vacuum toafford the mesylate intermediate as an oil (27.2 g, 99%). The mesylate(27.2 g, 48.2 mmol) and sodium azide (15.7 g, 241.0 mmol) in DMF (150ml) was heated with stirring at 70° C. for 12 h. The reaction mixturewas cooled to room temperature, diluted with water (750 mL), andextracted with ethyl acetate. Combined organic layers were washed withwater, brine, and dried (MgSO₄). Solvent was removed under vacuum andthe crude product purified by silica gel column chromatography (eluent:30% ethyl acetate in hexanes) to afford the azide product as a whitesolid. Yield 18.1 g (73%). M.p. 77-79° C. [α]^(D)═=−114° (c=1,methanol). ¹H NMR.

5-Benzyloxycarbonylaminoindazole

Benzyl chloroformate (9.9 ml, ca. 66 mmol) in tetrahydrofuran (66 ml)was added dropwise with stirring to 5-aminoindazole (4.44 g, 33 mmol) intetrahydrofuran (150 ml) and pyridine (12.0 ml, 150 mmol) at −5° C. Themixture was allowed to warm to room temperature, stirred for 4 h, andconcentrated under vacuum. Ethyl acetate (100 ml) and water (150 ml)were added, and the aqueous layer was extracted with ethyl acetate(2×100 ml). The combined organic laters were washed with 0.3 N aq. HCl(2×100 ml), water, brine, and dried (MgSO₄). Solvent was removed undervacuum to afford the crude product as a mixture of two regioisomers. MS(m/z): 402.1 [M+H]⁺. 0.3 M lithium hydroxide monohydrate in methanol(250 ml, ca. 75 mmol) was added. The mixture was stirred at roomtemperature for 45 min and then carefully acidified with 6 N aq. HCluntil the pH of the solution was 2. The resulting product was filteredoff, washed with water and dried under vacuum to afford the desiredcompound. R_(t) 4.2 min. MS (m/z): 268.1 [M+H]⁺. ¹H NMR.

5-Benzyloxycarbonylamino-1-triphenylmethylindazole

5-Benzyloxycarbonylaminoindazole (0.534 g, 2 mmol) was stirred withtrityl chloride (0.556 g, 2 mmol) and tetrabutylammonium iodide (0.074g, 0.2 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.42 ml, 3mmol) for 3 days at room temperature. Solvent was removed under vacuum,and the solid residue was triturated with methanol (3 ml). The solid waswashed with a mixture of methanol-water (5:1, ca. 15 ml) and dried undervacuum to afford the desired product. Yield 0.73 g (72%). ¹H NMR.

5-[5-(R)-Hydroxymethyloxazolidine-2-one-3-yl]-1-triphenylmethylindazole

1 M Lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.1 mL, 1.1mmol) was added dropwise with stirring at −78° C. to5-benzyloxycarbonylamino-1-tritylindazole (0.510 g, 1 mmol) intetrahydrofuran (10 mL) under nitrogen atmosphere. The mixture wasstirred at −78° C. for 1.5 h. (R)-Glycidyl butyrate (0.160 mL, 1.2 mmol)was added dropwise with stirring. The mixture was allowed to warm tor.t. overnight. Saturated aq. NH₄Cl (10 mL) was added, and the mixturewas extracted with EtOAc (2×20 mL). The combined organic layers werewashed with water (10 mL), brine (10 mL), and dried (MgSO₄). Solvent wasevaporated to 3 mL, and the residue was triturated with hexanes (50 mL).White crystalline product was filtered off, washed with hexanes, anddried in vacuo. Yield 0.440 g (93%). MS (m/z): 232.1 [M-Trt]⁻. ¹H NMR.

5-[5-(S)-Azidomethyloxazolidine-2-one-3-yl]-1-triphenylmethylindazole

Methanesulfonyl chloride (0.066 ml, 0.85 mmol) was added dropwise withstirring to a solution of5-[5-(R)-hydroxymethyloxazolidine-2-one-3-yl]-1-triphenylmethylindazole(0.300 g, 0.63 mmol) and triethylamine (0.18 ml, 1.3 mmol) indichloromethane (7.0 ml) at −30° C. over 5 minutes. The reaction mixturewas stirred at 5° C. for 2 h and quenched with water (15 ml). Ethylacetate (20 ml) was added, and the organic layer was washed with water,brine, and dried (MgSO₄). Solvent was removed under vacuum to afford amesylate intermediate. The mesylate and sodium azide (0.205 g, 3.15mmol) in DMF (4 ml) was heated with stirring at 75° C. for 4 h. Thereaction mixture was cooled to room temperature, diluted with water (ca.10 ml), and extracted with ethyl acetate (2×15 ml). The combined organiclayers were washed with water, brine, and dried (MgSO₄). Solvent wasremoved under vacuum to afford the desired product as off-whitecrystals. Yield 0.31 g (95%). MS (m/z): 257.1 [M-Trt]⁻. ¹H NMR.

BAL Aldehyde Resin

4-(4-Formyl-3,5-dimethoxyphenoxy)butyric acid (9.33 g, 34.8 mmol),pyridine (15 ml), and diisopropylcarbodiimide (3.00 ml, 19.1 mmol) indichloromethane (135 ml) were stirred at room temperature for 1 h.Tentagel S—NH, resin (Rapp Polymere, 0.29 mmol/g, 8.7 mmol) was added,and the mixture was agitated at room temperature overnight. The resinwas filtered, washed liberally with MeOH and dichloromethane and driedunder vacuum.

5-[5-(S)-Acetamidomethyloxazolidine-2-one-3-yl]-1-indazole

Tetrahydrofuran (1.0 mL) was added to the mixture of5-[5-(S)-azidomethyloxazolidine-2-one-3-yl]-1-triphenylmethylindazole(0.065 g, 0.13 mmol, ca. 3 eq. with respect to the resin reagent),triphenylphosphine (0.034 g, 0.13 mmol), and BAL aldehyde resin (150 mg,ca. 0.044 mmol). The mixture was stirred at r.t. for 2 h. A rubberseptum was replaced with a teflon-coated cap, and the mixture wasagitated at 75° C. for ca. 10 h. A tetrahydrofuran-triethylorthoformatemixture (1:1, 1 mL) was added to the resulting imine resin, followed by0.5 M NaBH₃CN (0.5 mL, 0.25 mmol). The mixture was agitated at roomtemperature for 3 h. The resulting amine resin was washed liberally withMeOH and dichloromethane, and dried under vacuum. An aceticanhydride-pyridine-dichloromethane solution (1 to 1.5 to 3, 4 mL) wasadded, and the mixture was agitated for 2 h (until negative ninhydrinetest indicated completion of the acylation). The trityl protection wasremoved by treatment with 1% TFA in DCM (2×4 mL, 15 min), and theproduct was cleaved with 60% TFA in DCM (2 mL) over 2 h. HPLC purity forthe cleaved product was 90% (Rt 2.95 min). Solvent was removed undervacuum, and the product was purified by preparative silica gel TLC(eluent: dichloromethane-MeOH 5: 1). Yield 7.0 mg (58%). R_(t) 2.9 min.(given below). MS (m/z): 275.1 [M+H]⁺. ¹H NMR.

BAL Resin Immobilized5-(S)-Aminomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one

Triphenylphosphine (0.130 g, 0.496 mmol) was added to a mixture of BALaldehyde resin (0.57 g, 0.165 mmol) and5-(S)-azidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one(0.154 g, 0.496 mmol) in THF (3 ml) at room temperature. The mixture wasstirred at room temperature for 2 h, and then at 75° C. for 16 h. Themixture was cooled to room temperature, and 1M sodium cyanoborohydridein THF (0.99 ml, 0.992 mmol) was added in one portion. The reactionmixture was agitated for 8 h. The resulting amine resin was washedliberally with methanol and dichloromethane and dried under vacuum.

BAL Resin Immobilized5-(S)-Acetamidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one

Acetic anhydride-pyridine-dichloromethane solution (1 to 1.5 to 3, 4 mL)was added to BAL resin immobilized5-(S)-aminomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one,and the mixture was agitated for ca. 2 h (until negative ninhydrine testindicated completion of the acylation). The resin was filtered, washedliberally with methanol and dichloromethane and dried under vacuum.

5-(S)-Acetamidomethyl-3-[4′-formyl-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-dimethoxymethyl-3′-fluorophenyl]-oxazolidine-2-one(0.100 g, 0.029 mmol) was suspended in 60% trifluoroacetic acid indichloromethane (2 ml) for 2 h at room temperature. The mixture wasfiltered, and supernatant was evaporated under vacuum to give the crudeproduct. The crude product was purified by preparative HPLC to affordthe desired product as an oil. Yield 4.9 mg, (60%). R_(t) 3.0 min. MS(m/z): 281.1 [M +H]⁺. ¹H NMR.

BAL Resin Immobilized5-(S)-Aminomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Triphenylphosphine (7.61 g, 29.0 mmol) was added to a mixture of BALaldehyde resin (33.3 g, 9.67 mmol) and5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one(9.76 g, 29.0 mmol) in tetrahydrofuran (170 ml) under nitrogen at roomtemperature. The mixture was agitated at room temperature for 2 h andthen at 75° C. for 16 h. The mixture was cooled to room temperature, and1 M sodium cyanoborohydride in THF (58.0 ml, 58.0 mmol) was added in oneportion. The reaction mixture was agitated for 8 h. The resulting amineresin was filtered, washed liberally with methanol and dichloromethane,and dried under vacuum.

BAL Resin Immobilized5-(S)-Aminomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one

A mixture of 1 M chlorotrimethylsilane in dichloromethane (290 ml, 0.29mol) and 1M phenol in dichloromethane (290 ml, 0.29 mol) was added toBAL resin immobilized5-(S)-aminomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one,and the reaction mixture was agitated at room temperature for 36 h. Theresulting acid resin was filtered, washed liberally with methanol anddichloromethane, and dried under vacuum.

General Procedure for the Synthesis of Immobilized5-(S)-Acylaminomethyl-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-ones

A selected carboxylic acid (18.0 mmol), pyridine (1.46 ml,18.0 n-tmol)and diisopropylcarbodiimide (1.35 ml, 9.90 mmol) in a mixture ofdimethylformamide-dichloromethane (4:1, 8 ml) were stirred at roomtemperature for 1 h. An appropriate BAL resin immobilized5-(S)-aminomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (1.80mmol) was added and the mixture was agitated at room temperature for 16h (or until ninhydrine test indicated a completion of the acylation).The resin was filtered, washed liberally with dimethylformamide, MeOH,dichloromethane, and dried under vacuum.

5-(S)-Acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one

Acetic anhydride-pyridine-dichloromethane solution (1:1.5:3, 200 mL).was added to an immobilized5-(S)-acylaminomethyl-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one(33.3 g, 9.67 mmol), and the mixture was agitated overnight. The resinwas filtered, washed liberally with methanol and dichloromethane anddried under vacuum. The acylated resin (0.100 g, 0.029 mmol) wassuspended in 60% trifluoroacetic acid in dichloromethane for 2 h at roomtemperature. The mixture was filtered, and the supernatant wasevaporated under vacuum to give a white solid which was washed withether and dried under vacuum. Yield 7.6 mg (88%); mp 252-253° C. ¹H NMR.

BAL Resin Immobilized5-(S)-Acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Pentafluorophenyl trifluoroacetate (7.10 ml, 41.3 mmol) was added to amixture of BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(20.4 g, 5.90 mmol) and pyridine (8 ml) in N-methylpyrrolidine-2-one (35ml). The reaction mixture was agitated at room temperature for 16 h. Theresin was filtered, washed with N-methylpyrrolidine-2-one anddichloromethane, and dried under vacuum. The resin was analyzed bycleavage with 60% trifluoroacetic acid in dichloromethane (2 ml per0.100 g. 0.029 mmol of the resin, 2 h). The resulting supernatant wasevaporated under vacuum to give the released pentafluorophenyl ester asa white solid. The solid was purified by preparative TLC (eluent 10%MEOH in dichloromethane). Yield 8.0 mg (60%); m.p. 172-173° C. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(4″-morpholinophenylamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.029 mmol) was agitated with 4-morpholinoaniline (0.155 mg,0.87 mmol) in 10% pyridine in dimethylformamide (2 ml) for 24 h. Theresin was filtered and washed liberally with dimethylformamide, MeOH,DCM, and dried under vacuum. The dry resin was cleaved in 60%trifluoroacetic acid in dichloromethane (2 ml) for 2 h at roomtemperature. The supernatant was evaporated under vacuum, and the crudeproduct was purified by preparative TLC (eluent: 10% methanol indichloromethane to give product as a white solid. Yield 6.6 mg (50%). MS(m/z): 457.2 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(3″-pyridylamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.029 mmol) was agitated with 3-aminopyridine (0.082 mg, 0.87mmol) in 10% pyridine in dimethylformamide (2 ml) for 24 h. The resinwas filtered and washed liberally with dimethylformamide, MeOH, DCM, anddried under vacuum. The dry resin was cleaved in 60% trifluoroaceticacid in dichloromethane (2 ml) for 2 h at room temperature. Thesupernatant was evaporated under vacuum, and the crude product waspurified by preparative TLC (eluent: 10% methanol in dichloromethane) togive the product as a white solid. Yield 4.3 mg (40%). MS(m/z): 373.1[M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(4″-morpholino)carbonyl-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.029 mmol) was agitated with morpholine (0.10 ml, 0.116 mmol)in N-methylpyrrolidine-2-one (2 ml) for 16 h. The resin was filtered andwashed liberally with N-methylpyrrolidine-2-one, MeOH, dichloromethane,and dried under vacuum. The dry resin was cleaved in 60% trifluoroaceticacid in dichloromethane (2 ml) for 2 h at room temperature. The resinwas filtered, the filtrate evaporated under vacuum, and the crudeproduct was purified by preparative TLC (eluent: 10% MeOH indichloromethane) to give the product as a white solid. Yield 5.6 mg(53%); m.p. 210-211° C. ¹H NMR.

BAL Resin Immobilized Weinreb Amide:5-(S)-Acetamidomethyl-3-[4′-N-methoxy-N-methylaminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(1.00 g, 0.29 mmol) was agitated with N-methoxy-N-methylaminehydrochloride (0.59 g, 6.0 mmol) and triethylamine (0.84 ml, 6.0 mmol)in N-methylpyrrolidine-2-one for 16 h at room temperature. The resin wasfiltered, washed liberally with N-methylpyrrolidine-2-one, MeOH,dichloromethane, and dried under vacuum. A small portion of the resin(ca. 10 mg) was cleaved in 60% trifluoroacetic acid in dichloromethane(0.20 ml) for 2 h at room temperature. The supernatant was concentratedunder vacuum to afford the cleaved Weinreb amide as an oil. R_(t) 2.8min. MS (m/z): 340.1 [M+H]⁺. ¹H NMR.

BAL Resin Immobilized Aldehyde5-(S)-Acetamidomethyl-3-[4′-formyl-3′-fluorophenyl]-oxazolidine-2-one

0.1 M Lithium aluminum hydride in tetrahydrofuran (0.52 ml) was addeddropwise with stirring to BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-N-methoxy-N-methylaminocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.150 g, 0.044 mmol) in tetrahydrofuran (2 ml) at −78° C. The mixturewas agitated at −78° C. for 4-6 h. It was then allowed to warm to roomtemperature overnight. The resin was filtered, washed liberally withtetrahydrofuran, MeOH, dichloromethane, and dried under vacuum. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-formyl-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-formyl-3′-fluorophenyl]-oxazolidine-2-one(0.150 g, 0.0435 mol) was cleaved with 60% trifluoroacetic acid indichloromethane (2 ml) for 2 h at room temperature. Supernatant wasevaporated under vacuum to give the crude product as an oil. MS (m/z):281.1 [M +H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-acetyl-3′-fluorophenyl]oxazolidine-2-one

3.0 M Methylmagnesium iodide in diethyl ether (0.022 ml, 0.066 mmol) isadded dropwise with stirring to BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-N-methoxy-N-methylaminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.150 g, 0.044 mmol) in tetrahydrofuran (2 ml) at −78° C. The mixtureis agitated at 78° C. for 5-10 h, and then allowed to warm to roomtemperature overnight. The resin is filtered, washed liberally withtetrahydrofuran, MeOH, dichloromethane, and dried under vacuum. Theresulting ketone resin is cleaved with 60% trifluoroacetic acid indichloromethane (2 ml) for 2 h at room temperature. The supernatant isevaporated under vacuum to afford the desired product.

BAL Resin Immobilized Acyl Azide5-(S)-Acetamidomethyl-3-[4′-azidocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Method A: with azidotrimethylsilane and tetrabutylammonium fluoride. 1 MTetrabutylammonium fluoride in tetrahydrofuran (0.609 ml, 0.609 mmol)was added to azidotrimethylsilane (0.34 ml, 2.6 mmol) in tetrahydrofuran(3.5 ml), and the mixture was kept at room temperature for 0.5 h. Theresulting solution was added to BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one,and the mixture was agitated at room temperature for 4-5 h. The acylazide resin was filtered, washed with dichloromethane and acetone. IR(cm-′): 2136 (N₃). The resin was further analyzed by cleavage with 60%trifluoroacetic acid in dichloromethane (2 ml per 0.100 g, 0.029 mmol ofthe resin, 2 h). The resulting supernatant was evaporated under vacuumto give the released acyl azide product. R_(t) 3.3 min. IR (cm⁻¹): 2138(N₃). MS (m/z): 278.1 [M−N₂+H]⁺. ¹H NMR.

Method B: with tetrabutylammonium azide. BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(Tentagel HL NH₂ resin, 1.00 g, ca. 0.40 mmol/g) was agitated withtetrabutylammonium azide (0.797 g, 2.8 mmol) in tetrahydrofuran (10 ml)for 5 h at room temperature. The resin was filtered, washed liberallywith dichloromethane and acetone, and dried under vacuum.

BAL Resin Immobilized Protected Amine5-(S)-Acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized acyl azide5-(S)-acetamidomethyl-3-[4′-azidocarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.75 g, 0.22 mmol) and (9-fluorenyl)methanol (1.18 g, 6.0 mmol) intetrahydrofuran (7.0 ml) were agitated at 80° C. for 4 h. The resultingFmoc-protected amine resin was washed with tetrahydrofuran, MeOH,dichloromethane, and dried under vacuum.

5-(S)-Acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluoro-phenyl]-oxazolidine-2-one

Method A. BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.200 g) was cleaved with 60% trifluoroacetic acid in dichloromethane(2 ml) for 2 h. The resulting supernatant was evaporated under vacuum togive the released Fmoc carbamate product. R_(t) 4.3 min. MS (m/z): 490.2[M+H]⁺. ¹H NMR.

Method B. 9-Fluorenylmethyl chloroformate (0-039 g, 0.15 mmol) indichloromethane (0.300 ml) and pyridine (0.05 ml, 0.62 mmol) was addedto BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]oxazolidine-2-one, andthe mixture was agitated at room temperature for 2 h. The resultingresin was worked up and cleaved as described above for Method A. R_(t)4.3 min. MS (m/z): 490.2 [M+H]⁺. ¹H NMR.

BAL Resin Immobilized Amine5-(S)-Acetamidomethyl-3-[4′-amino-3′-fluorophenyl]-oxazolidine-2-one

Method A. BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(ca. 0.200 g) was deprotected with 20% piperidine in dimethylformamide(2 ml) for 20 min. The resulting amine resin was washed liberally withMeOH, dichloromethane, and dried under vacuum. The resin was analyzed bycleavage with 60% trifluoroacetic acid in dichloromethane (2 ml, 2 h).The resulting supernatant was evaporated under vacuum to give thereleased amine product. MS (m/z): 268.1 [M+H]⁺. ¹H NMR.

Method B. BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)-oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.200 mg), azidotrimethylsilane (0.240 ml, 1.74 mmol) and catalytictetrabutylammonium fluoride (0.05 ml, 0.05 mmol) in tetrahydrofuran (5ml) were agitated at 80° C. for 4 h. The resulting amine resin waswashed liberally with MeOH and dichloromethane. It was dried undervacuum and analyzed as described above for Method A. MS (m/z): 268.1[M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(para-nitrobenzene)sulfonamido-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]-oxazolidine-2-one(0.200 g) was agitated with para-nitrobenzenesulfonyl chloride (0.108 g,0.50 mmol) in dichloromethane (2.0 ml) with N-methylmorpholine (0.200ml) for 14 h at room temperature. The resulting sulfonamide resin wasfiltered, washed liberally with dimethylformamide, MeOH,dichloromethane, and dried under vacuum. The dry resin was cleaved with60% trifluoroacetic acid in dichloromethane (2 ml, 2 h). The resultingsupernatant was evaporated under vacuum to give the sulfonamide product.MS (m/z): 453.1 [M+H]⁺. ¹H NMR.

N¹-(9-Fluorenylmethoxycarbonyl)-N²-[4′-(5″-(S)-acetamidomethyloxazolidine-2-one-3″-yl)-3′-fluorophenyl]thiourea

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-amino-3′-fluorophenyl]-oxazolidine-2-one(0.200 g) was agitated with 9-fluorenylmethoxycarbonylisocyanate (0.140g, 0.50 mmol) in dichloromethane (2.0 ml) for 14 h at room temperature.The resulting thiourea resin was filtered, washed liberally withdimethylformamide, MeOH, dichloromethane, and dried under vacuum. Thedry resin was cleaved with 60% trifluoroacetic acid in dichloromethane(2 ml, 2 h). The resulting supernatant was evaporated under vacuum togive the sulfonamide product. R_(t) 4.5 min. MS (m/z): 549.1 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-[4′-(4″-phenylthiazole-2″-yl)amino-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilizedN¹-(9-Fluorenylmethoxycarbonyl)-N²-[4′-(5″-(S)-acetamidomethyloxazolidine-2-one-3″-yl)-3′-fluorophenyl]thioureawas deprotected with 20% piperidine in dimethylformamide (2 ml) for 40min, filtered, washed liberally with MeOH, dichloromethane, and driedunder vacuum. 2-Bromoacetophenone (0.100 g, 0.50 mmol) intetrahydrofuran (2.0 ml) was added, and the mixture was agitated at roomtemperature for 2 h. The resulting thiazole resin was washed liberallywith MeOH, dichloromethane, and dried under vacuum. The dry resin wascleaved with 60% trifluoroacetic acid in dichloromethane (2 ml, 2 h).The resulting supernatant was evaporated under vacuum to give thethiazole product. R_(t) 3.9 min. MS (m/z): 427.1 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(5′-amino-4′-cyanooxazole-2′-yl)-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)-oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g) was agitated with aminomalonitrile tosylate (0.253 g, 1 mmol)in a mixture of dry pyridine and N-methylpyrrolidine-2-one (1:1, 2.0 ml)at 60° C. for 8-10 h. The resulting aminooxazole resin was washedliberally with MeOH, dichloromethane, and dried under vacuum. The dryresin was cleaved with 60% trifluoroacetic acid in dichloromethane (2ml, 2 h). The resulting supernatant was evaporated under vacuum to givethe oxazole product. R_(t) 3.2 min. MS (m/z): 360.1 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one

Triphenylphosphine (2.82 g, 10.8 mmol) was added portionwise to asolution of5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one(5.00 g, 9.79 mmol) in THF (40 mL), and the mixture stirred for 2 h atroom temperature. Water (1.41 mL, 78.3 mmol) was added, and the mixtureheated at 40° C. overnight. Solvent was removed under vacuum, and theoily residue dissolved in dichloromethane (50 mL). Acetic anhydride(4.62 ml, 49.0 mmol) and pyridine (7.92 ml, 97.9 mmol) were added, andthe mixture stirred for 8 h at r.t. Solvent was removed under vacuum andthe crude product purified by silica gel flash column chromatography(eluent: 30% ethyl acetate in hexanes) to give the product as a foam(4.98 g, 97 %); MS: 527 [M+H]⁺. ¹H NMR.

BAL Resin Immobilized5-(S)-Aminomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one

Diisopropylcarbodiiimide (4.24 ml, 27.0 mmol) aws added to4-(4-formyl-3,5-dimethoxyphenoxy)butyric acid (13.19 g, 49.2 mmol) andpyridine (20 mL) in dichloromethane (190 mL), and the mixture wasstirred at room temperature for 1 h. Tentagel S—NH₂ resin (RappPolymere, 30.0 g, 12.3 mmol) was added, and the mixture agitated at roomtemperature overnight. Resulted BAL resin was filtered, washed liberallywith methanol and dichloromethane and dried under vacuum.Triphenylphosphine (7.97 g, 0.0304 mol) was added to a mixture of aboveBAL aldehyde resin (50.9 g, 0.0209 mol) and5-(S)-azidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(15.5 g, 30.4 mmol) in THF (200 ml) under nitrogen at r.t. (roomtemperature). The mixture was agitated at r.t. for 2 h and then heatedat 75° C. for 16 h. The mixture was cooled to r.t., and 1M sodiumcyanoborohydride in THF (62.7 ml, 62.7 mmol) was added. The mixture wasagitated for 8 h at r.t. The resin was filtered, washed liberally withmethanol and dichloromethane and dried under vacuum.

BAL Resin Immobilized5-(S)-Acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilized5-(S)-Aminomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]-oxazolidine-2-one(5.00 g, 2.05 mmol) was suspended in 5% trifluoroacetic acid and 2.5%triisopropylsilane in dichloromethane (50 mL), and the mixture wasagitated for 1 h. The resin was filtered and the procedure repeated withfresh 5% trifluoroacetic acid and 2.5% triisopropylsilane indichloromethane (50 mL) for another 30 minutes. The resin was filteredand washed liberally with dichloromethane. Resulted thiol resin wasimmediately suspended in a mixture of acetic anhydride (20 mL) andpyridine (30 mL) in DCM (50 mL), and the mixture was agitated overnightat r.t. The resin was filtered, washed liberally with dichloromethaneand dried under vacuum.

5-(S)-Acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-one.(0.15 g, 0.041 mmol) was suspended in 60% trifluoroacetic acid indichloromethane for 2 at r.t. Supernatant was evaporated under vacuumand the crude product was purified by TLC (10% methanol indichloromethane). Yield 8.7 mg (67%). MS: 327 [M+H]⁺. ¹H NMR.

Ester Oxazolidinone Derivatives General Procedures for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-ones

Method A. 4.37 M Sodium methoxide in methanol (0.0927 ml, 0.405 mmol)was added to an appropriate BAL resin immobilized5-(S)-amidomethyl-3-[4′-acylthio-3′-fluorophenyl]oxazolidine-2-one(prepared as described above; 0.15 g, 0.041 mmol) in a polar aproticsolvent (preferably, N-methylpyrrolidine-2-one, 1.5 mL), and the mixturewas agitated for 5-25 min (typically completed within 5 min foracetylated compounds). Optionally, an organic base was used instead ofsodium methoxide (e.g., tetramethylguanidine or alkylamine). Anappropriate alkylating or (hetero)arylating reagent (0.8-1.6 mmol) wasadded, and the mixture agitated at r.t. for 12-36 h (typically, completeovernight). The resin wash washed thoroughly withN-methylpyrrolidine-2-one, dichloromethane, and methanol. The resin wassuspended in 60% trifluoroacetic acid in dichloromethane and agitated atroom temperature for 2 h. Supernatant was evaporated under vacuum andthe crude product purified by TLC (methanol-dichloromethane mixtures).

Method B. 5% Trifluoroacetic acid and 2.5% triisopropylsilane indichloromethane (2.0 mL) was added to5-(S)-acetamidomethyl-3-[4′-triphenylmethylthio-3′-fluorophenyl]oxazolidine-2-one(0.10, 0.19 mmol), and the mixture was stirred at r.t. for 1 h. and themixture stirred for 1 h at room temperature. Solvent was removed undervacuum, and the residue dissolved in methanol (3 mL). An appropriatealkylating or (hetero)arylating reagent (19-0.38 mmol) was added,followed by dropwise addition of 4.37 M sodium methoxide in methanol(0.087 ml, 0.380 mmol). Optionally, an organic base was used instead ofsodium methoxide (e.g., tetramethylguanidine or alkylamine). The mixturewas stirred at 20-70° C. for 2-24 h (typically, 2 h at r.t.). Solventwas removed under vacuum and the crude product purified by TLC(methanol-dichloromethane mixtures).

5-(S)-Acetamidomethyl-3-[4′-(6″-chloropyridazine-3″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-onewith 3,6-dichloropyridazine (0.12 g, 0.81 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 3.9 mg (24%). MS: 397 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-[4′-(4′,6″-dimethoxy-1″,3″,5″-triazine-2″-yl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-onewith 2-chloro-4,6-dimethoxy-1,3,5-triazine (0.1 g, 0.81 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 6.1 mg (36%). MS: 424 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-[4′-(5″-nitropyridine-2″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-onewith 2-chloro-5-nitropyridine (0.13 g, 0.81 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 7.0 mg (44%). MS: 407 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-(4′-[2″-(4′″-morpholino)ethyl]thio-3′-fluorophenyl)-oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-onewith 4-(2-chloroethyl)morpholine hydrochloride (0.28 g, 0.81 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 2.4 mg (15%). MS: 398 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-[4′-(pyridine-3″-yl)methylthio-3′-fluorophenyl)-oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazolidine-2-onewith 3-(chloromethyl)pyridine hydrochloride (0.13 g, 0.81 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 3.6 mg (24%). MS: 376 [M+H]⁺.

5-(S)-Acetamidomethyl-3-(4′-methylthio-3′-fluorophenyl)oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazoli-dine-2-onewith methyl iodide (0.05 mL, 0.81 mmol) in N-methylpyrrolidine-2-one (1mL). The synthesis was performed at r.t. overnight, and the crudecleaved product purified by TLC (eluent: 10% methanol indichloromethane). Yield 6.3 mg (52%). MS: 299 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-methylthiazole-4″-yl)methylthio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-acetylthio-3′-fluorophenyl]oxazoli-dine-2-onewith 4-chloromethyl-2-methylthiazole hydrochloride (0.15 g, 0.81 mmol)in N-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.overnight, and the crude cleaved product purified by TLC (eluent: 10%methanol in dichloromethane). Yield 6.9 mg (43%). MS: 396 [M+H]⁺. ¹HNMR.

5-(S)-Acetamidomethyl-3-[4′-(1″,2″,4″-oxadiazole-3″-yl)methylthiazole-4″-yl)methylthio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]-oxazolidine-2-onewith 3-chloromethyl-1,2,4-oxadiazole (0.045 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.043 g (62%). MS: 367 [M+H]⁺.

5-(S)-Acetamidomethyl-3-[4′-(methoxycarbonyl)methylthio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith methyl bromoacetate (0.058 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.056 g (83%). M.p. 119-120° C. MS: 357 [M+H]⁺.¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-methoxyethyl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 2-chloroethyl methyl ether (0.036 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.034 g (52%). MS (m/z): 343 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(3″-nitrothien-2″-yl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 2-chloro-3-nitrothiophene (0.062 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.066 g (85%). M.p. 194-195° C. MS (m/z): 412[M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(acetylmethyl)thio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith chloroacetone (0.062 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1mL). The synthesis was performed at r.t. for 2 h. The crude product waspurified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.039 g(61%). MS (m/z): 341 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 2-bromoethanol (0.048 g, 0.38 mmol) in N-methylpyrrolidine-2-one (1mL). The synthesis was performed at r.t. for 2 h. The crude product waspurified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.045 g(72%). MS (m/z): 329 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(5″-carboxypyridine-3″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith t-butyl 2-chloronicotinate (0.081 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The intermediate t-butyl ester of the product was deprotectedwith 20% trifluoroacetic acid in dichloromethane (1 mL, 2 h at r.t.).Solvent was evaporated under vacuum, and the crude product washed withdiethyl ether. Yield 0.050 g (65%). MS (m/z): 406 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-(4′-cyclopropylmethylthio-3′-fluorophenyl)oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith chloromethyl cyclopropane (0.051 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.053 g (82%). MS (m/z): 339 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(3″-cyanoethyl)thio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 3-bromopropionitrile (0.051 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.032 g (50%). MS (m/z): 338 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(5″-nitrothiazole-2″-yl)thio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 2-bromo-5-nitrothiazole (0.079 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.061 g (78%). MS (m/z): 413 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(5″-phenyl-1″,2″,4″-oxadiazole-3″-yl)methylthio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom 5-(S)-acetamido-methyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 3-chloromethyl-5-phenyl-1,2,4-oxadiazole (0.074 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.040 g (47%). MS (m/z): 443 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(3″-methoxycarbonvlpropane-2″-one-1″-yl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamido-methyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith methyl 4-chloroacetoacetate (0.057 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.027 g (35%). MS (m/z): 399 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-chloroethyl)thio-3′-fluorophenyl]oxazolidi-ne-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 1-bromo-2-chloroethane (0.055 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.047 g (72%). MS (m/z): 347 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(1″-ethoxycarbony-1″,1″-dimethyl)methylthio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith ethyl 2-bromoisobutyrate (0.074 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.061 g (80%). MS (m/z): 399 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-diethoxyphosphinoyl)ethylthio-3′-fluorophenyl]oxazo-lidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith diethyl (2-bromoethyl)phosphonate (0.093 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.043 g (50%). MS (m/z): 449 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(thiocyano)methylthio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamidomethyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith chloromethyl thiocyanate (0.041 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.022 g (35%). MS (m/z): 324 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(3″-methyltetrahydrofuran-2″-one-3″-yl)thio-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazoli-dine-2-onesfrom5-(S)-acetamido-methyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith α-bromo-α-methyl-γ-butyrolactone (0.068 g, 0.38 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.035 g (48%). MS (m/z): 383 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-diethylamino)ethylthio-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-(substituted)thio-3′-fluorophenyl]oxazolidine-2-onesfrom5-(S)-acetamido-methyl-3-[4′-(triphenylmethyl)lthio-3′-fluorophenyl]oxazolidine-2-onewith 2-(diethylamino)ethyl chloride hydrochloride (0.065 g, 0.38 mmol)and 4.37 M sodium methoxide (0.174 mL, 0.760 mmol) inN-methylpyrrolidine-2-one (1 mL). The synthesis was performed at r.t.for 2 h. The crude product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.011 g (15%). MS (m/z): 383 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-hydroxyethyl)sulfinyl-3′-fluorophenyl]oxazolidine-2-one

Sodium periodate (0.014 g, 0.065 mmol) in water (0.5 mL) was added to5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]-oxazo-lidine-2-one(0.020 g, 0.061 mmol) in-methanol (1 mL), and the mixture was stirred atr.t. overnight. Solvent was removed under vacuum, and the residuedissolved in ethyl acetate (ca. 5 mL). Resulting solution was washedwith water, brine, and dried (MgSO₄). Solvent was removed under vacuum,and the crude product purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.018 g (86%). MS (m/z): 345 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(2″-hydroxyethyl)sulfonyl-3′-fluorophenyl]-oxazolidine-2-one

30% Hydrogen peroxide (0.023 mL, 0.244 mmol) was added to5-(S)-acetamidomethyl-3-[4′-(2″-hydroxyethyl)thio-3′-fluorophenyl]oxazoli-dine-2-one(0.020 g, 0.061 mmol) in acetic acid (1 mL), and the mixture was stirredat 60° C. overnight. Solvent was removed under vacuum, and the residuedissolved in ethyl acetate (ca. 5 mL). Resulting solution was washedwith water, brine, and dried (MgSO₄). Solvent was removed under vacuum,and the crude product purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.017 g (77%). M.p. 162-163° C. MS (m/z): 361[M+H]⁺. ¹H NMR.

Ester Oxazolidinone Derivatives5-(S)—(N-Acetylaminomethyl)-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]-oxazolidine-2-one

Triphenylphosphine (0.521 g, 1.99 mmol) was added portionwise to asolution of5-(S)—(N-azidomethyl)-3-[4′-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.607 g, 1.80 mmol) in THF (10 ml), and the mixture was stirred at r.t.for 2 h. Water (0.259 ml, 14.4 mmol) was added, and the mixture heatedat 40° C. overnight. Solvent was removed under vacuum. The oily residuewas dissolved in a mixture of acetic anhydride (0.849 ml, 9.00 mmol) andpyridine (0.146 ml, 18.0 mmol) in dichloromethane (10 ml) and stirredfor 4 h. Solvent was removed under vacuum, and the crude product waspurified by TLC (eluent: 10% methanol in dichloromethane). Yield 0.62 g(98 %). MS (m/z): 353 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acetylaminomethyl)-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one

5-(S)—(N-Acetylaminomethyl)-3-[4′-(4″-(tert-butoxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(6.20 g, 17.5 mmol) was dissolved in 20% trifluoroacetic acid indichloromethane, and the mixture stirred at r.t. overnight. Solvent wasremoved under vacuum, and the residue triturated with ether to giveproduct as a white solid. Yield 5.20 g (99%). M.p. 252-253° C.; MS: 297[M+H]⁺. ¹H NMR.

General Procedures for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-[alkyl[or(hetero)aryl]oxylcarbonyl-3′-fluorophenyl]-oxazolidine-2-ones

Method A. An appropriate5-(S)—(N-acylaminomethyl)-3-[4′-(4″-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-oneresin of the type 5 (0.1 mmol; prepared from resin 4 via two stepacylation with an appropriate N-acylating reagent, and subsequentPfp-activation as described above) was mixed with a selected alcoholreagent (1-3 mmol, typically, 1-2 mmol) and 4-dimethylaminopyridine(0.2-1 mmol; typically, 1 mmol) in aprotic solvent(N,N-dimethylformamide, dichloromethane, or dimethylsulfoxide;preferably, N,N-dimethylformamide, 4-6 mL). The mixture was agitated at20-70° C. for 6-48 h (typically, at r.t. overnight). The resin wasfiltered, washed liberally with N,N-dimethylformamide, dichloromethane,methanol, dried in vacuo, and cleaved with 60% trifluoroacetic acid indichloromethane (5 ml, 2 h). Resulting supernatant was evaporated invacuo, and the crude product purified by HPLC or TLC.

Method B. An appropriate alkylating reagent (0.35-1.2 mmol; preferably,1 mmol) was added to5-(S)—(N-acetamidomethyl)-3-[4′-(pentafluoro-phenyloxy)carbonyl-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol) and potassium carbonate (0.187 g, 1.35 mmol) inN,N-dimethylformamide (2 mL), and the mixture agitated at 20-80° C. for6-24 h (typically, at r.t. overnight). Water (ca. 10-15 mL) was added,and the mixture was extracted with ethyl acetate (ca. 3×20 mL). Combinedorganic solvents were washed with water, brine, and dried (MgSO₄).Solvent was evaporated in vacuo, and the crude product purified by HPLCor TLC.

5-(S)—(N-Acetylaminomethyl)-3-[4′-cyclopropylmethoxycarbonyl-3′-fluoro-phenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-[alkyl[or(hetero)aryl]oxy]carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BALresin5-(S)—(N-acylaminomethyl)-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) and hydroxymethylcyclopropane (0.144 g, 2 mmol) with4-dimethylaminopyridine (1 mmol) in N,N-dimethylformamide (4 mL).Reaction performed at r.t. overnight. Crude cleaved product was purifiedby TLC (eluent: 10% methanol in dichloromethane). MS (m/z): 350 [M+H]⁺.Aternatively, the compound was made according to Method B ofaforementioned General Procedure from5-(S)—(N-acetamidomethyl)-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one(0.100 g, 0.34 mmol) and (bromomethyl)cyclopropane (0.098 mL, 1 mmol).Reaction was performed at 70° C. overnight. Crude product was purifiedby TLC (eluent: 10% methanol in dichloromethane). Yield 0.100 g (85%).MS (m/z): 350 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-methoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-[alkyl[or(hetero)aryl]oxy]-carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)—(N-acetamido-methyl)-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol) and methyl iodide (0.063 mL, 1 mmol). Reaction wasperformed at r.t. overnight. Crude product was purified by TLC (eluent:10% methanol in dichloromethane). Yield 104 mg (99%). MS (m/z): 311[M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-isopropoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-[alkyl[or(hetero)aryl]oxy]-carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)—(N-acetamido-methyl)-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol) and 2-bromopropane (0.095 mL, 1 mmol). Reaction wasperformed at 70° C. overnight. Crude product was purified by TLC(eluent: 10% methanol in dichloromethane). Yield 105 mg (92%). MS (m/z):339 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-ethoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method B of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-[alkyl[or(hetero)aryl]oxy]-carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)—(N-acetamido-methyl)-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol) and ethyl iodide (0.081 mL, 1 mmol). Reaction wasperformed at r.t. overnight. Crude product was purified by TLC (eluent:10% methanol in dichloromethane). Yield 107 mg (98%). MS (m/z): 325[M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-[(N-isoprolpylidene)imino]oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)—(N-acetamidomethyl)-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol), 4-(dimethylamino)-pyridine (0.041 g, 0.34 mmol),diisopropylcarbodiimide (0.053 ml, 0.34 mmol) and acetone oxime (0.025g, 0.34 mmol) in N,N-dimethyformamide (2 ml) was stirred at r.t.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate. Organic layers were washed with brine, and dried(MgSO₄). Solvent was remove under vacuum, and the residue was purifiedby TLC (eluent: 10% methanol in dichloromethane). Yield 0.098 g (83%).MS (m/z): 352 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-(pyridine-3″-yl)methoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one

A mixture of5-(S)—(N-acetamidomethyl)-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.100 g, 0.34 mmol), 4-(dimethylamino)pyridine (0.041 g, 0.34 mmol),diisopropylcarbodiimide (0.053 ml, 0.34 mmol) and 3-pyridylcarbinol(0.033 g, 0.34 mmol) in N,N-dimethyformamide (2 ml) was stirred at r.t.overnight. The reaction mixture was diluted with water and extractedwith ethyl acetate. Organic layers were washed with brine, and dried(MgSO₄). Solvent was remove under vacuum, and the residue was purifiedby TLC (eluent: 10% methanol in dichloromethane). Yield 0.094 g (72%).MS (m/z): 388 [M+H]⁺. ¹H NMR.

Amide Oxazolidinone Derivatives General Procedures for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-[(un)substitutedamino]carbonyl-3′-fluorophenyl]-oxazolidine-2-ones 7

Method A. An appropriate5-(S)—(N-acylaminomethyl)-3-[4′-(4″-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-oneresin of the type 5 (prepared from BAL resin immobilized5-(S)-aminomethyl-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one 4 viatwo step acylation with an appropriate N-acylating reagent, andsubsequent Pfp-activation as described above (0.029 mmol) was agitatedwith a selected amine compound (0.1-0.2 mmol; preferably 0.116 mmol) ina polar non-protic solvent such as N-methylpyrrolidine-2-one,N,N-dimethylformamide (2-4 ml) for 16-48 h at 25-70° C. (preferably, at60° C. overnight) containing 10-20% v/v of an organic base (pyridine,2,6-lutidine, or diisopropylethylamine). Optionally, dimethylsulfoxide(0.5-1 mL) was added for less soluble amine reagents. Also optionally,functionalized amines (such as amino acids or amino alcohols) werepre-dissolved with addition of a silylating reagent (such asbis-trimethylsilylacetamide, 0.2-0.6 mmol) prior to addition to theresin, and the reaction was performed under inert gas atmosphere(nitrogen). Resulted resin was filtered and washed liberally withN-methylpyrrolidine-2-one, MeOH, dichloromethane, and dried undervacuum. The dry resin was cleaved in 60% trifluoroacetic acid indichloromethane (2 ml) for 2 h at room temperature. The resin wasfiltered, the filtrate evaporated under vacuum, and crude productpurified by preparative TLC (MeOH-dichloromethane) or reverse phaseHPLC.

Method B. 60% Trifluoroacetic acid in dichloromethane (5 mL) was addedto5-(S)-azidomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.336 g, 1 mmol), and the solution kept at r.t. for 1 h. Solvents wereremoved in vacuo to afford5-(S)-azidomethyl-3-[4′-carboxy-3′-fluorophenyl-]oxazolidine-2-one dried(0.280 g, 99%). N-Trimethylsilyl-N,N-diethylamine (0.23 mL, 1.2 mmol)was added to above product in dry dichloromethane (3 mL) under nitrogenatmosphere, and the solution stirred for 15 min. Solvents and excessreagent were removed in vacuo, and residue dissolved in dichloromethane(4 mL). The solution was cooled to ca. 0° C., and oxalyl chloride (1.5mmol, 0.13 mL) was added dropwise, followed by catalyticN,N-dimethylformamide (ca. 0.01 mL). The mixture was alllowed to warm upto r.t., and stirred at r.t. for another 2 h. Solvents were removed invacuo, and the resulting5-(S)-azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]-oxazolidine-2-oneredissolved in dry aprotic solvent (preferably, tetrahydrofuran,pyridine, or acetonitrile, 3-10 mL). Resulted solution (0.8 mL, ca. 0.2mmol) was added to an appropriate amine reagent (1 mmol) in aproticsolvent (preferably, acetonitrile, or pyridine, 1-5 mL) optionallycontaining an organic base (preferably, pyridine, 0.5-2 mL). The mixturewas stirred at r.t. for 1-5 h. Solvent was removed in vacuo, andresulting5-(S)-azidomethyl-3-[4′-(substituted)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-onewas typically washed with water, and dried in vacuo. Triphenylphosphine(0.262 g, 1.0 mmol) in tetrahydrofuran (10 mL) was added to above azideintermediate, and the mixture stirred at 45-55° C. ° C. for 2 h. Water(0.5 mL) was added, and the mixture stirred overnight at 50-60° C.Solvents were removed in vacuo, and resulting crude amine intermediatestypically washed with excess diethyl ether. Aprotic solvent was added(preferably, tetrahydrofuran, 5-15 mL) was added, followed by pyridine(0.25-0.5 mL) and acetic anhydride (0.2-0.5 mL), and the mixture stirredat r.t. for 0.5-2 h (typically, 1 h). Solvents were removed in vacuo,and resulting product typically washed with excess diethyl ether anddried in vacuo.

Method C. N,N-Diisopropyl-N-ethylamine (0.34 mL, 2 mmol) was added to5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one(0.296 g, 1 mmol) and a coupling reagents, [preferably,O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)] in a polar aprotic solvent such asN,N-dimethylformamide (3 mL) and tetrahydrofuran (2 mL), and thesolution was kept at r.t. for 20 min. An appropriate amine (1 mmol) wasadded, followed by an organic base (preferably,N,N-diisopropyl-N-ethylamine, 0.17 mL, 1 mmol), and the mixture stirredat 20-60° C. for 1-24 h (typically, at r.t. for 1-2 h). Additional base(typically, 1 mmol) was added when amine salts were employed.Optionally, catalytic 4-dimethylaminopyridine (0.05-0.2 mmol) was addedfor acylation of less reactive amines. Volatile organic solvents wereremoved in vacuo. The product was typically isolated by precipitationwith excess of water (5-60 mL), or by extraction from aqueous solutionswith ethyl acetate (20-40 mL). In the latter case, organic layers werewashed with saturated aqueous sodium bicarbonate, water, 3% aqueouscitric acid, water, brine, and dried (MgSO₄). Organic solvent wasremoved in vacuo, and the product further purified by washing withexcess of diethyl ether, or by crystallization from an appropriatesolvent (typically, methanol or ethanol).

Method D. N-Ethyl-N′-(3-diethylaminopropyl)carbodiimide (0.92 g, 4.8mmol) was added to 5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one (1.18 g, 4.0 mmol) and pentafluorophenol (0.81 g, 4.4mmol) in N,N-dimethylfomamide (50 mL) and the solution stirred at r.t.for 24 h. Most of solvent was removed in vacuo, the residue dissolved inacetonitrile (ca. 40 mL), and this solution added dropwise with stirringinto 3% aqueous citric acid (ca. 150 mL). Precipitated5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxa-zolidine-2-onewas filtered off, washed with water, and dried in vacuo (yield 1.30 g,70%; M.p. 172-173° C.; Rt 5.2 min). The resulting ester (1 mmol) wasdissolved in a polar solvent (preferably, tetrahydrofuran oracetonitrile 10 mL), and an appropriate amine (1-5 mmol) added. Themixture was stirred at r.t. for 1-10 h (typically, 1-2 h). Solvent andexcess reagent were removed in vacuo, and the product purified bychromatography or crystallization from an appropriate solvent.

5-(S)-Acetamidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Method A. Prepared according to Method A of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-oneand 2-chloro-5-amino-pyridine in 10% pyridine inN-methylpyrrolidine-2-one (70^(oi)C, 48 h). MS: 407 [M+H]⁺. To obtainthe hydrochloride form of this compound, above material (41 mg, ca. 0.1mmol) was dissolved in methanol (10 mL) with 2M HCl in 1,4-dioxane (5mL). Resulted solution was filtered, solvents removed in vacuo, and thecrude salt washed with excess of diethyl ether.

Method B. Prepared according to Method B of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluoro-phenyl]-oxazolidine-2-ones by amide couplingof5-(S)-azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-oneand 2-chloro-5-aminopyridine in pyridine (3 mL, r.t., 1 h). Solvent wasremoved in vacuo, and resulting5-(S)-azidomethyl-3-[4′-(6″-chloropyridine-3″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-onewas washed with water (5×3 mL mL), and dried in vacuo.Triphenylphosphine (0.262 g, 1.0 mmol) in tetrahydrofuran (10 mL) wasadded to above azide intermediate, and the mixture stirred at 45° C. for2 h. Water (0.5 mL) was added, and the mixture stirred overnight at 50°C. Solvents were removed in vacuo, and resulting crude amineintermediate washed with excess diethyl ether. Tetrahydrofuran (15 mL)was added, followed by pyridine (0.25 mL) and acetic anhydride (0.2 mL),and the mixture stirred at r.t. for 1 h. Solvents were removed in vacuo,and resulting product washed with excess diethyl ether. MS: 407 [M+H]⁺.¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(thiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Method A. Prepared according to Method A of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-oneand 2-aminothiazole in 10% pyridine in N-methylpyrrolidine-2-one (r.t.,24 h). MS: 379 [M+H]⁺. Rt 3.8 min. To obtain the hydrochloride form ofthis compound, above material (38 mg, ca. 0.1 mmol) was dissolved inmethanol (10 mL) with 2M HCl in 1,4-dioxane (5 mL), filtered, solventsremoved in vacuo, and the residue washed with excess of diethyl ether.

Method B. Prepared according to Method C of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]-oxazolidin-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 2-aminothiazole (0.10 g, 1 mmol). The synthesis was performed atr.t. overnight. Tetrahydrofuran was removed in vacuo, and the residueadded to water (60 mL). Resulted suspension was kept at r.t. for 1 h,filtered, and the product washed with excess water and dried in vacuo.

5-(S)-Acetamidomethyl-3-[4′-(4,5-dimethylthiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Method A. Prepared according to Method A of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-oneand 2-amino-4,5-dimethylthiazole in 10% pyridine inN-methylpyrrolidine-2-one (r.t., 24 h). MS: 407 [M+H]⁺. Rt 4.1 min. ¹HNMR.

Method B. Prepared according to Method C of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 2-amino-4,5-dimethyl-thiazole. The synthesis was performed at r.t.for 3 h. MS: 407 [M+H]⁺. Rt 4.1 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(pyrimidine-4″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Method A. Prepared according to Method A of the the General Procedursefor Preparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-oneand 4-aminopyrimidine in 10% pyridine in N-methylpyrrolidine-2-one (70°C., 48 h). MS: 374 [M+H]⁺. Rt 3.4 min. ¹H NMR.

Method B. Prepared according to Method C of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 4-aminopyrimidine. The synthesis was performed at r.t. for 24 h.Water (15 mL) was, and the mixture kept at r.t. for 3 days to allow forproduct crystallization. MS: 374 [M+H]⁺. Rt 3.4 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(thiazole-2″-yl)aminocarbonyl-3′-fluorophenyl-oxazolidine-2-one

Method A. Prepared according to the General Procedure for preparation of5-(S)—(N-acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)-oxycarbonyl-3′-fluorophenyl]oxa-zolidine-2-oneand 5-chloro-2-aminothiazole in 10% pyridine inN-methylpyrrolidine-2-one (70° C., 48 h). MS: 413 [M+H]⁺. ¹H NMR.

Method B. Prepared according to Method B of the General Procedures forPreparation of 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluoro-phenyl]-oxazolidine-2-ones by amide couplingof5-(S)-azidomethyl-3-[4′-chlorocarbonyl-3′-fluorophenyl]oxazolidine-2-oneand 5-chloro-2-aminothiazole hydrochloride in tetrahydrofuran (ca. 4 mL)and acetonitrile (2.5 mL) with pyridine (0.5 mL). The mixture wasstirred for 2 h at r.t., and methanol (ca. 7 mL) was added. Resultedprecipitate of5-(S)-azidomethyl-3-[4′-(thiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-onewas filtered, washed with methanol (8 mL), diethyl ether, and dried invacuo. Triphenylphosphine (0.31 g, 1.2 mmol) inN-methylpyrrolidine-2-one (1.25 mL) and tetrahydrofuran (1.25 mL) wasadded to above azide intermediate, and the mixture stirred at r.t. for 2h. Water (0.1 mL) was added, and the mixture stirred overnight at 50° C.Solvents were removed in vacuo, and resulting crude amine intermediatewashed with excess diethyl ether. Tetrahydrofuran (8 mL) was added,followed by pyridine (0.5 mL) and acetic anhydride (0.5 mL), and themixture stirred at r.t. for 30 min. Solvents were removed in vacuo, andresulting product washed with excess diethyl ether, water (2×3 mL),diethyl ether, and dried in vacuo. MS: 413 [M+H]⁺. ¹H NMR.

5-(S)-(Methylthio)acetamidomethyl-3-[4′-(6″-chloropyridine-3″-yl)amino-carbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-(methylthio)acetamidomethyl-3-[4′-(pentafluorophenyl)-oxycarbonyl-3′-fluo-rophenyl]-oxazolidine-2-oneand 2-chloro-5-aminopyridine. MS: 453 [M+H]⁺. To obtain thehydrochloride form of this compound, above material (45 mg, ca. 0.1mmol) was dissolved in methanol (10 mL) with 2M HCl in 1,4-dioxane (5mL), filtered, solvents removed in vacuo, and the residue washed withexcess of diethyl ether.

5-(S)-Acetamidomethyl-3-[4′-(benzothiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 2-aminobenzothiazole. The synthesis was performed at r.t. over 3 h.MS: 429 [M+H]⁺. Rt 4.6 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(6″-methoxybenzothiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 6-methoxy-2-aminobenzothiazole. The synthesis was performed at r.t.over 3 h. MS: 459 [M+H]⁺. Rt 4.7 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(6″-methoxybenzothiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)-carbonyl-3′-fluorophenyl]-oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 5-methylthio-3-aminopyridine. The synthesis was performed at r.t.overnight. MS: 419 [M+H]⁺. Rt 3.8 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(4″-amino-5″-phenylthiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 2,4-diamino-5-phenylthiazole hydrobromide. The synthesis wasperformed at r.t. overnight. MS: 470 [M+H]⁺. Rt 4.5 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(5″-ethylthio-1,3,4-thiadiazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 5-ethylthio-2-amino-1,3,4-thiadiazole. MS: 440 [M+H]⁺. R_(t) 4.4min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(1,3,4-thiadiazole-2″-yl)aminocarbo-nyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method C of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-oneand 2-amino-1,3,4-thiadiazole. MS: 380 [M+H]⁺. R_(t) 3.6 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(imidazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-(methylthio)acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.400 g, ca. 0.1 mmol) and 2-aminoimidazole sulfate (0.234 g, 2 mmol).The amine reagent was pre-dissolved in a mixture of 10% pyridine inN-methylpyrrolidine-2one (4 mL), bis-(trimethylsilyl)acetamide (0.5 mL),and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.15 mL, 1 mmol) at 70° C. over2 h. Coupling with the resin reagent was performed at r.t. over 48 h.The crude product after cleavage from resin was purified byreverse-phase HPLC. MS: 362 [M+H]⁺. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(1,3,4-triazole-2″-yl)aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-(methylthio)acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.400 g, ca. 0.1 mmol) and 2-amino-1,3,4-triazole (0.168 g, 2 mmol).The amine reagent was pre-dissolved in a mixture of 10% pyridine inN-methylpyrrolidine-2-one (4 mL), bis-(trimethylsilyl)acetamide (0.5 mL)at 70° C. over 2 h. Coupling with the resin reagent was performed at 60°C. over 48 h. The crude product after cleavage from resin was purifiedby reverse phase HPLC. MS: 363 [M+H]⁺. R_(t) 3.1 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(pyridine-3″-yl-1″-oxide)aminocarbonyl-3′-fluorphenyl]-oxazolidine-2-one

30% Aqueous hydrogen peroxide (0.05 mL) was added to5-(S)-acetamidomethyl-3-[4′-(3″-pyridylamino)carbonyl-3′-fluoro-phenyl]-oxazolidine-2-one(7 mg, ca. 0.02 mmol) and methylrhenium trioxide (MTO, 0.9 mg) inN-methylpyrrolidine-2-one (0.15 mL). The mixture was stirred for 30 minat r.t., and solvents removed in vacuo (0.1 Torr, r.t.). The crudeproduct was washed with methanol (0.5 mL) and diethyl ether. MS: 389[M+H]⁺. R_(t) 3.3 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-hydroxyaminocarbonyl-3′-fluorophenyl]-oxazolidine-2-one

Prepared according to Method D of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamidomethyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.046 g, 0.1 mmol) and O-trimethylsilylhydroxylamine (0.052 mL, ca. 0.5mmol) in tetrahydrofuran (1 mL). The synthesis was performed for 2 h atr.t. Diethyl ether (4 mL) was added, the precipitated product washedwith diethyl ether, tetrahydrofuran (2×0.5 mL), excess ether, and driedin vacuo. MS: 312 [M+H]⁺. R_(t) 2.8 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-methylaminocarbonyl-3′-fluorophenyl]-oxazo-lidine-2-one

Prepared according to Method D of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from5-(S)-acetamido-methyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one(0.046 g, 0.1 mmol) and 2 M methylamine in tetrahydrofuran (1 mL, 2mmol). The synthesis was performed at r.t. for 45 min. Diethyl ether (4mL) was added, the precipitated product washed with diethyl ether,tetrahydrofuran (2×0.5 mL), excess ether, and dried in vacuo. MS: 310[M+H]⁺. R_(t) 3.2 min. ¹H NMR.

5-(S)-trans-[4″-Methoxyimino)cinnamoyl]methyl-3-[4′-aminocarbonyl-3′-fluorophenyl]oxazolidine-2-one

Prepared according to Method A of the General Procedures for Preparationof 5-(S)—(N-Acylaminomethyl)-3-[4′-(4″-(un)substitutedamino)carbonyl-3′-fluorophenyl]oxazolidine-2-ones from BAL resinimmobilized5-(S)-[trans-(4″-methoxyimino)cinnamoyl)methyl-3-[4′-(pentafluorophenyl)oxycarbonyl-3′-fluorophenyl]oxazolidine-2-one(0.400 g, ca. 0.1 mmol) and 2 M ammonia in 1,4-dioxane (5 mL, ca. 10mmol). The synthesis was performed at r.t. overnight. The crude productafter cleavage from resin was purified by reverse phase HPLC. MS: 441[M+H]⁺. ¹H NMR.

General Procedure for Preparation of5-(S)-Amidomethyl-3-[4′-[(un)substituted1″,3″,5″-triazine-2″-yl]amino-3′-fluorophenyl]oxazolidine-2-one

An appropriate BAL resin immobilized5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.06-0.1 mmol) was deprotected by agitation with 20% piperidine in DMF(4 mL) for 45 min. Resulted aniline resin was washed liberally withN,N-dimethylformamide, dichloromethane, methanol, and dried in vacuo. Asolution of an appropriate halogen-substituted triazine reagent(preferably, a chlorotriazine derivative, 1-3 mmol) and organic base(preferably N,N-diisopropyl-N-ethylamine or 2,6-di-t-butylpyridine, 3-6mmol) in aprotic solvent (preferably, N-methylpyrrolidine-2-one,dichloromethane, 1,4-dioxane, or acetonitrile) was added, and themixture agitated at 0-80° C. for 12-36 h (typically, at 0-40° C.overnight). Resulted aniline resin was washed liberally withN,N-dimethylformamide, dichloromethane, methanol, and dried in vacuo.When the triazine oxazolidinone contained more than one halogensubstituent, the reaction was optionally repeated using amine, thiol, oralcohol reagents as described above (40-80° C., 12-36 h). Washed and dryresin was cleaved with 60% trifluoroacetic acid in dichloromethane (5ml, 2 h). Resulted supernatant was evaporated in vacuo, and the crudeproduct purified by HPLC or TLC.

5-(S)-Acetamidomethyl-3-[4′-(4″-chloro-6″-1″,2″,3″-triazine-2″-yl)amino-3′-fluorophenyl]oxazolidine-2-one

BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophen-yl]oxazolidine-2-one(0.06 mmol) was deprotected by agitation with 20% piperidine in DMF (4mL) for 45 min. Resulted aniline resin was washed liberally withN,N-dimethylformamide, dichloromethane, methanol, and dried in vacuo. Asolution of cyanuric trichloride (0.194 g, 1.0 mmol) and2,6-di-t-butylpyridine (0.36 mL, 1.5 mmol) in dichloromethane (4 mL) wasadded, and the mixture agitated at r.t. for 24 h. Resulted aniline resinwas washed liberally with N,N-dimethylformamide, dichloromethane,methanol, and dried in vacuo. 0.5 M Ammonia in 1,4-dioxane (5 mL, 2.5mmol) was added, and the mixture agitated at r.t. for 24 h. The resinwas washed liberally with N,N-dimethylformamide, dichloromethane,methanol, dried in vacuo, and cleaved with 60% trifluoroacetic acid indichloromethane (5 ml, 2 h). Resulting supernatant was evaporated invacuo, and the crude product purified by preparative TLC (eluentmethanol—dichloromethane 1:10). MS: 396 [M+H]⁺. R_(t) 3.6 min. ¹H NMR.

5-(S)-Acetamidomethyl-3-[4′-(4″,6″-dimethoxy-1″,3″,5″-triazine-2″yl)amino-3′-fluoro-phenyl]oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)-Amidomethyl-3-[4′-[(un)substitutedtriazinyl]-3′-fluorophenyl]oxazolidine-2-one from BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophe-nyl]oxazolidine-2-one(0.06 mmol) and 2-chloro-4,6-dimethoxytriazine (0.275 g, 1.5 mmol).Reaction of the immobilized aniline and the triazine reagent wasrepeated twice in a mixture of N-methylpyrrolidine-2-one anddichloromethane (1:1, 4 mL) at r.t. overnight. The crude cleaved productwas purified by preparative TLC (eluent methanol—dichloromethane 1:10).MS: 407 [M+H]⁺. ¹H NMR.

Acylamino Oxazolidinone Derivatives General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-acylamino-3′-fluorophenyl]oxazolidine-2-ones

An appropriate BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)ami-no-3′-fluorophen-yl]oxazolidine-2-one(0.1 mmol) was deprotected by agitation with 20% piperidine in DMF (4mL) for 45 min. Resulting aniline resin was washed liberally withN,N-dimethylformamide, dichloromethane, methanol, and dried in vacuo.Separately, N,N-diisopropyl-N-ethylamine (3-6 mmol; typically, 3 mmol)was added to selected carboxylic acid (1-2 mmol; typically, 1 mmol) anda coupling reagent [preferably,O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate or diisopro-pylcarbodiimide; 3-6 mmol; typically, 3mmol) in a polar aprotic solvent such as N,N-dimethylformamide (7-10 mL,and the mixture agitated at r.t. for 20-30 min. Resulted solution of thepre-activated acid reagent was added to above aniline resin, and themixture agitated at 20-60° C. for 6-24 h (typically, at r.t. overnight).The resin was washed liberally with N,N-dimethylformamide,dichloromethane, methanol, dried in vacuo, and cleaved with 60%trifluoroacetic acid in dichloromethane (5 ml, 2 h). Resultingsupernatant was evaporated in vacuo, and the crude product purified byHPLC or TLC.

5-(S)—(N-Acetamidomethyl)-3-[4′-acetamido-3′-fluorophenyl]oxazolidine-2-ones

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-acylamino-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol). The intermediate aniline was acylated with the mixture ofacetic anhydride—pyridine—dichloromethane (1:1.5:3, 2 mL). Crude cleavedproduct was purified by TLC (eluent: 10% methanol in dichloromethane).Yield 0.014 g (46%). MS: 310 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-(2″,4″-thiazole-5″-yl)carbonylamino-3′-fluorophenyl]oxazolidine-2-ones

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-acylamino-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol). Acylation was performed with2,4-dimethylthiazole-5-carboxylic acid (0.157 g, 1 mmol) pre-activatedwith diisopropylcarbodiimide (0.086 mL, 0.55 mmol) and pyridine (0.081mL, 1 mmol) in a mixture of N,N-dimethylformamide—dichloromethane 4:1 (2mL) at r.t. overnight. Crude cleaved product was purified by TLC(eluent: 10% methanol in dichloromethane). Yield 0.028 g (68%). MS: 407[M+H]⁺. ¹H NMR.

5-(S)—(N-Acetamidomethyl)-3-[4′-(pyridine-3″-yl)carbonylamino-3′-fluorophenyl]oxazolidine-2-ones

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-acylamino-3′-fluorophenyl]oxazolidine-2-onesfrom BAL resin immobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophen-yl]oxazolidine-2-one(0.02 mmol). Acylation was performed with nicotinic acid (0.049 g, 0.40mmol) pre-activated withO-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (0.160 g, 0.20 mmol) andN,N-diisopropyl-N-ethylamine (0.21 mL, 1.20 mmol) inN,N-dimethylformamide (1 mL) at r.t. overnight. Crude cleaved productwas purified by TLC (eluent: 10% methanol in dichloromethane). Yield0.023 g (62%). MS: 373 [M+H]⁺. ¹H NMR.

Sulfonamido Oxazolidinone Derivatives General Procedure for Preparationof5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-ones

An appropriate BAL resin immobilized5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)ami-no-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) was deprotected by agitation with 20% piperidine in DMF (4mL) for 45 min. Resulted aniline resin was washed liberally withN,N-dimethylformamide, dichloromethane, methanol, and dried in vacuo.The resin was suspended in 20% pyridine in dichloromethane (2 mL), and asolution of selected sulfonyl chloride reagent (1-2 mmol; preferably,1.25 mmol) in dichloromethane was added. The mixture was agitated at20-40° C. for 12-36 h (typically, at r.t. overnight). Resin wasfiltered, washed with methanol, and suspended in 0.1 M lithium hydroxidemonohydrate in methanol (4 mL). The mixture was agitated at r.t. for30-90 min (typically, for 90 min). The resin was filtered, washedliberally with N,N-dimethylformamide, dichloromethane, methanol, driedin vacuo, and cleaved with 60% trifluoroacetic acid in dichloromethane(5 ml, 2 h). Resulted supernatant was evaporated in vacuo, and the crudeproduct purified by HPLC or TLC.

5-(S)—(N-Acylaminomethyl)-3-[4′-methylsulfonamido-3′-fluorophenyl]-oxazolidine-2-ones

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-onesfrom5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) and methanesulfonyl chloride (0.2 mL, 1.25 mmol). The crudecleaved product was purified by TLC (eluent: 10% methanol indichloromethane). Yield 0.022 g (65%). MS (m/z): 346 [M+H]⁺. ¹H NMR.

5-(S)—(N-Acylaminomethyl)-3-[4′-(benzo-2″,1″,3″thiadiazole-4″-yl)sulfon-amido-3′-fluorophenyl]oxazolidine-2-ones

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-onesfrom5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) and benzo-2,1,3-thiadiazole-4-sulfonyl chloride (0.295 g,1.25 mmol). The crude cleaved product was purified by TLC (eluent: 10%methanol in dichloromethane). Yield 0.024 g (52%). MS (m/z): 466 [M+H]⁺.

5-(S)—(N-Acetamidomethyl)-3-[4′-(4″,5″-dibromothioiphene-2″-yl)sulfonami-do-3′-fluorophenyl]oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-onesfrom from BAL resin immobilized5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophen-yl]oxazolidine-2-one(0.1 mmol) and 2,3-dibromothiophene-5-sulfonyl chloride (0.43 g, 1.25mmol). The crude cleaved product was purified by TLC (eluent: 10%methanol in dichloromethane). Yield 0.044 g (77%). ¹H NMR. MS (m/z): 572[M+H]⁺.

5-(S)—(N-Acetamidomethyl)-3-[4′-(6″-chloroimidazo[2,1-b]thiazole-5″-yl)sulfonamido-3′-fluorophenyl]oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-onesfrom from BAL resin immobilized5-(S)-acylamino-methyl-3-[4′-(9″-fluorenylmethoxycarbonyl)-amino-3′-fluorophenyl]oxazolidi-ne-2-one(0.1 mmol) and 6-chloro-imidazo[2,1-b]thiazole-5-sulfonyl chloride (0.32g, 1.25 mmol). The crude cleaved product was purified by TLC (eluent:10% methanol in dichloromethane). Yield 0.019 g (39%). ¹H NMR. MS (m/z):572 [M+H]⁺.

5-(S)—(N-Acetamidomethyl)-3-[4′-(2″-acetamido-4″-methylthiazole-5″-yl)-sulfonamido-3′-fluorophenyl]oxazolidine-2-one

Prepared according to the General Procedure for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluorophenyl]oxazolidine-2-onesfrom from BAL resin immobilized5-(S)-acylamino-methyl-3-[4′-(9″-fluorenylmethoxycarbonyl)-amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) and 2-acetamido-4-methyl-5-thiazolesulphonyl chloride (0.32g, 1.25 mmol). The crude cleaved product was purified by TLC (eluent:10% methanol in dichloromethane). Yield 0.025 g (52%). ¹H NMR. MS (m/z):486 [M+H]⁺.

5-(S)—(N-Acetamidomethyl)-3-[4′-(N-methyl)methylsulfonamido-3′-fluorophenyl]-oxazolidine-2-one

BAL resin immobilized5-(S)—(N-acetamidomethyl)-3-[4′-methylsulfonamido-3′-fluorophenyl]oxazolidine-2-onewas prepared from from BAL resin immobilized5-(S)-acylaminomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophenyl]oxazolidine-2-one(0.1 mmol) and methanesulfonyl chloride (0.2 mL, 1.25 mmol) as describedabove in the synthesis of5-(S)—(N-acetamidomethyl)-3-[4′-methylsulfonamido-3′-fluorophenyl]oxazolidine-2-one.N-Methylpyrrolidi-ne-2-one (2 ml) was added, followed by methyl iodide(0.16 ml, 2.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.37 ml, 2.5mmol). The mixture was agitated overnight at r.t. The resin wasfiltered, washed thoroughly with dichloromethane and methanol, and driedunder vacuum. Oroduct was cleaved with 60% trifluoroacetic acid indichloromethane (5 mL, 2 h), solvent removed under vacuum, and the crudeproduct purified by TLC (eluent: 10% methanol in dichloromethane). Yield0.017 g (48%). ¹H NMR. MS (m/z): 360 [M+H]⁺.

Procedures for Preparation of 3-(Heteroaryl)oxazolidine-2-oneDerivatives 5-(S)-Azidomethyloxazolidine-2-one

5-(R)-Chloromethyloxazolidine-2-one (prepared according to [Danielmeieret al. Efficient Pathways to (R)— and (S)-hydroxymethyl-2-oxazolidinoneand some derivatives. Tetrahedron: Asymmetry. 1995, vol. 6, pp.1181-1190] (5 mmol) is reacted with sodium azide (7-10 mmol) in acetone(ca. 40-50 mL) at r.t. for ca. 24 h (until the reaction is completed).Solids are filtered off, and supernatant evaporated under vacuum toafford the product which is immediately used for the next step.Optionally, the synthesis is performed in dry N,N-dimethylformamideunder inert atmosphere with sodium azide (5-10 mmol) ortetrabutylammonium azide (5-10 mmol), and the resulting solution of thecrude 5-(S)-azidomethyloxazolidine-2-one is employed for the next stepwithout solvent removal.

5-(S)-Azidomethyl-3-(heteroaryl)oxazolidine-2-ones and ApplicationThereof for Preparation of 3-(Heteroaryl)oxazolidine-2-ones

An appropriate heteroarylchloride or heteroarylbromide (e.g. pyridyl,pyrimidyl, thienyl, thiazolyl, or thiadiazolyl halide; 5 mmol) is addedto the solution of 5-(S)-azidomethyloxazolidine-2-one (ca. 5 mmol) indry N,N-dimethylformamide (ca. 30-50 mL) at 0-20° C. (typically, at10-15° C.), followed by addition of a strong base (typically, sodiumhydride, 5-15 mmol). The mixture is stirred at 20-120° C. for 2-24 h(typically, for 6 h at r.t.). Excess base is carefully quenched withacetic acid (to pH ca. 5-7), and most of the solvent is removed undervacuum. Water is added, and the mixture extracted with ethyl acetate.Combined organic layers are washed with water, 3% aq. citric acid,water, and the crude product purified by crystallization fromappropriate solvents or by silica gel chromatography. Resulted5-(S)-azidomethyl-3-(hetero-aryl)oxazolidine-2-ones are immobilized onBAL resin just as described above for the synthesis of BAL resinimmobilized5-(S)-aminomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]oxazolidine-2-one,and the polymeric reagents thus obtained are used for synthesis of3-(heteroaryl)oxazolidine-2-ones analogously to described aboveprocedures for the synthesis of respective3-(fluorophenyl)oxazolidinones.

5-(S)-Azidomethyl-3-[5′-methoxycarbonyl-6′-trifluoromethylpyrimidine-2′-yl]oxazolidine-2-one

The compound is prepared according to above protocol for the synthesisof 5-(S)-azidomethyl-3-heteroaryloxazolidine-2-ones from2-chloro-5-methoxycarbonyl-6-trifluoromethylpyrimidine (1 mmol) and5-(S)-azidomethyloxazolidine-2-one (1.2 mmol) in N,N-dimethylformamide(5 mL). The reaction is performed with 60% sodium hydride in oil (3mmol) at 15-20° C. for ca. 2 h. The crude product is purified by silicagel chromatography.

5-(S)-Azidomethyl-3-[5′-carboxy-6′-trifluoromethylpyrimidine-2′-yl]oxazoli-dine-2-one

0.2 M Lithium or sodium hydroxide in a mixture of tetrahydrofuran—water(ca. 10 mL, 2 mmol) is added to5-(S)-azidomethyl-3-[5′-methoxycarbonyl-6′-trifluoromethylpyrimidine-2′-yl]oxazolidine-2-one(1 mmol), and the mixture stirred at r.t. until the reaction iscompleted (by TLC analysis). Tetrahydrofuran is removed under vacuum, 3%aq. citric acid is added (to pH ca. 2-4), and the acid product isextracted with ethyl acetate. Organic layers are washed with water,brine, and dried (MgSO₄). Solvent removed under vacuum and the crudeproduct is purified by silica gel chromatography.

BAL Resin Immmobilized5-(S)-Aminomethyl-3-[5′-carboxy-6′-trifluoromethylpyrimidine-2′-yl]oxazolidine-2-oneand its Application its Preparation of 3-(Pyrimidyl)oxazolidine-2-ones

Triphenylphosphine (3 mmol) is added to a mixture of BAL aldehyde resin(0.3 mmol) and5-(S)-azidomethyl-3-[5′-hydroxy-6′-trifluoromethylpyrimidine-2′-yl]oxazolidine-2-one(3 mmol) in tetrahydrofuran (10 mL) with bis(trimethylsilyl)acetamide(ca. 6 mmol) under nitrogen at r.t. The mixture is agitated at roomtemperature for 2 h and then at 75° C. for 16 h. The mixture is cooledto room temperature, and 1M sodium cyanoborohydride in THF (6 mL, 6mmol) is added in one portion. The reaction mixture is agitated for 6-8h, resulted amine resin filtered, washed liberally with methanol anddichloromethane, and dried under vacuum. BAL resin immmobilized5-(S)-aminomethyl-3-[5′-carboxy-6′-trifluoromethylpyrimidine-2′-yl]oxazolidine-2-onethus obtained is further used for synthesis of3-(pyrimidyl)oxazolidine-2-ones just as described above for thesynthesis of respective 3-(fluorophenyl)oxazolidinones from BAL resinimmobilized5-(S)-aminomethyl-3-[4′-carboxy-3′-fluorophenyl]-oxazolidine-2-one.

3-(Pyridine-2-yl)oxazolidinone Derivatives t-Butyl 6-chloronicotinate

Thionyl chloride (25 mL) was added to 6-chloronicotinic acid (5.00 g,0.0317 mol) containing 1 drop of N,N-dimethylformamide, and the mixtureheated under reflux for 2 h. The solution was evaporated under vacuum,and residue thoroughly dried under vacuum. The acid chloride thusobtained was dissolved in tetrahydrofuran (50 mL), and 1 M lithiumt-butoxide in tetrahydrofuran (66.6 mL, 0.0666 mol) added dropwise atr.t. The mixture was stirred overnight, diluted with water (100 mL) andextracted with ethyl acetate. The extract was washed with sat. aqueousNaHCO₃, brine and dried (MgSO₄). Solvent was removed under vacuum toafford the pure ester as an off white solid. Yield 6.23 g (92%). ¹H NMR.MS (m/z): 214 [M+H]⁺.

3-(t-Butoxycarbonyl)-6-[(R)-propane-1,2-diol-3-yl]aminopyridine

A mixture of t-butyl 6-chloronicotinate (4.69 g, 0.0220 mol) and(R)-3-amino-1,2-propanediol (5.00 g, 0.0549 mol) in isopropanol (20 ml)was heated at 100° C. overnight. Solvent was removed under vacuum, andthe residue taken up in ethyl acetate, washed with water, brine, dried(MgSO₄), and evaporated to give nearly pure product as a yellow oil.Yield 5.90 g (99%). ¹H NMR. MS: 269 [M+H]⁺.

5-(R)-Hydroxymethyl-3-[3″-(t-butoxycarbonyl)pyridine-6″-yl]oxazolidine-2-one

Triethylamine (0.0518 mL, 0.558 mmol) was added to a solution of3-(t-butoxy-carbonyl)-6-[(R)-propane-1,2-diol-3-yl]aminopyridine (0.100g, 0.372 mmol) in dichloromethane (3 mL). The mixture was cooled in anice bath, and 20% phosgene in toluene (0.236 mL, 0.446 mmol) was addeddropwise with stirring. The reaction was allowed to warm to r.t. andstirred for at r.t. for 2 h. Water (3 mL) was added, and the organiclayer separated, washed with brine and dried (MgSO₄). Evaporation undervacuum afforded a white solid residue which was purified by flash columnchromatography (eluent: ethyl acetate—hexanes 1:1). Yield 0.093 g (85%).¹H NMR. MS (m/z): 295 [M+H]⁺.

5-(S)-Azidomethyl-3-[3″-(t-butoxycarbonyl)pyridine-6″-yl]oxazolidine-2-one

Methanesulfonyl chloride (1.38 mL, 0.0179 mol) was added dropwise withstirring to a solution of5-(R)-hydroxymethyl-3-[3′-(t-butoxycarbonyl)pyridine-6″-yl]oxazolidine-2-one(5.00 g, 0.0170 mol) and triethylamine (3.55 mL, 0.0255 mol) indichloromethane (50 mL) at 0° C. The reaction mixture was allowed towarm to r.t. and then poured into water. The organic layer wasseparated, washed with water, sat. aq. NaHCO₃, brine, and dried (MgSO₄).Solvent was removed under vacuum to afford the mesylate intermediate.The intermediate thus obtained was heated with sodium azide (5.53 g,0.085 mol) in N,N-dimethylformamide (ca. 40 mL) at 65° C. for 12 h. Thereaction mixture was diluted with water (ca. 100 mL) and extracted withethyl acetate. Organic layers was washed with water and brine, and dried(MgSO₄). The solvent was removed under vacuum and the residue purifiedby column chromatography (ethyl acetate—hexanes) to afford the pureproduct. Rt 5.0 min. ¹H NMR. MS (m/z): 320 [M+H]⁺.

5-(S)—(N-Acylaminomethyl)-3-[3″-[(un)substitutedaminolcarbonylpyridine-6″-yl]oxazolidine-2-ones

5-(S)-Azidomethyl-3-[3′-(t-butoxycarbonyl)pyridine-6″-yl]oxazolidine-2-oneis immobilized on BAL-type resin with triphenylphosphine and soodiumcyanoborohydride as described above for preparation of BAL resinimmobilized5-(S)-aminomethyl-3-[4′-tert-butoxycarbonyl-3′-fluorophenyl]-oxazolidine-2-one.The polymeric reagent thus obtained is deprotected as described for thepreparation of BAL resin immobilized5-(S)-aminomethyl-3-[4′-carboxy-3′-fluorophenyl]oxazolidine-2-one, andresulting BAL resin immobilized5-(S)—(N-acylaminomethyl)-3-(3″-carboxypyridine-6″-yl)oxazolidine-2-oneemployed for the synthesis of5-(S)—(N-acylaminomethyl)-3-[3″-[(un)substitutedamino]carbonylpyridine-6″-yl]-oxazolidine-2-ones analogously to theMethod A of the General Procedures for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-[(un)substitutedamino]-carbonyl-3′-fluorophenyl]oxazolidine-2-ones 7.

BAL Resin Immobilized5-(S)—(N-Acylaminomethyl)-3-[3″-(9′″-fluorenylmethoxycarbonyl)amino]pyridine-6″-yl]oxazolidine-2-onesand Application Thereof for Preparation of 3-(Pyridyl)oxazolidinones

The compound prepared from BAL resin immobilized5-(S)—(N-acylaminomethyl)-3-(3″-carboxypyridine-6″-yl)oxazolidine-2-onas described above in the procedure for preparation of BAL resinimmobilized5-(S)-acetamidomethyl-3-[4′-(9″-fluorenylmethoxycarbonyl)amino-3′-fluorophe-nyl]oxazolidine-2-one.The polymeric reagent thus obtained is further employed, e.g., forsynthesis of respective 3″-acylated and 3″-sulfonylated3-(pyridyl)oxazolidinones just as described above in the GeneralProcedures for Preparation of5-(S)—(N-Acylaminomethyl)-3-[4′-acylamino-3′-fluorophenyl]-oxazolidine-2-ones5-(S)—(N-Acylaminomethyl)-3-[4′-sulfonamido-3′-fluoro-phenyl]oxazolidine-2-ones[except that resulting products incorporate 3-(pyridyl)oxazolidinonegroup instead of 3-(fluorophenyl)oxazolidinone group].

Preparation of immobilized epoxide (12a). To PNP resin (23a) (0.5 g,0.77 mmol/g loading) at room temperature was added allylamine (125 μL,1.67 mmol) in 2 mL of DMF. The resin was shaken overnight and thenfiltered. It was sequentially washed with DMF and DCM. After being driedin vacuo, the olefin resin (24a, 100 mg) was treated with mCPBA (80%, 72mg, 0.355 mmol) in DCM for 16 hrs. The reaction mixture was filtered,and the resin was washed with DCM. Epoxide resin 12a was provided upondrying in vacuo. See FIG. 25.

General method for the reaction of immobilized epoxide 5 with an amine.To epoxide resin 12a at room temperature was added lithium triflate(LiOTf, 5 equivalents) and the amine (1 M in ACN, 10 equivalents). Themixture was shaken at room temperature for 15 hours, providing resinbound amino alcohol. The resin was filtered and sequentially washed withACN and DMF. Treatment of the resin with TFA in DCM cleaved the aminoalcohol. The reaction mixture was filtered and the resin washed withDCM. Concentration of the filtrate in vacuo provided the free aminoalcohol.

Amino Alcohol Library. To an array of individual reaction chambers eachcontaining particles or beads of epoxide resin 12a (25 mg) in ACN wasadded lithium triflate and an amine unit (0.5 mmol). The amine units ofTable 2 were used. The array was shaken at room temperature for 15hours, filtered and sequentially washed with ACN and DMF. The aminoalcohol resin was cleaved upon treatment with TFA. The resin wasfiltered and washed with DCM. A plurality of amino alcohols was providedupon concentration of the filtrate array in vacuo.

General method for the preparation of oxazolidinones. To the resin boundamino alcohol 8a in DMF at room temperature was added N-methylmorpholine(NMM, 10 equivalents) and carbonyldiimidazole (CDI, 5 equivalents). Theresin was shaken for 10 hrs, filtered and sequentially washed with DMFand DCM. Treatment of the resin with TFA in DCM for 0.5 hr cleaved theoxazolidinone. The resin was filtered and washed with DCM. The filtratewas concentrated in vacuo to yield an oxazolidinone amine residue 16a.Semi-preparative HPLC provided pure oxazolidinone amine.

Acetylation of Oxazolidinone Amine. To the crude oxazolidinone amineresidue 16a in DCM at room temperature was added pyridine (30equivalents) and acetic anhydride (20 equivalents). The solution wasstirred for 2 hrs and concentrated in vacuo. The oxazolidinone acetamideresidue was purified by HPLC to provide pure oxazolidinone acetamide.

Oxazolidinone Library. To an array of individual reaction chambers eachcontaining particles or beads of epoxide resin 12a (25 mg) in CAN wasadded lithium triflate and an amine unit (0.5 mmol). The amine units ofTable 2 were used. The array was shaken at room temperature for 15hours, filtered and sequentially washed with CAN and DMF. To the arrayof amino alcohol resin was added NMM (10 equivalents) and CDI (5equivalents). The array was shaken at room temperature for 10 hours,filtered and sequentially washed with DMF and DCM. The oxazolidinoneresin was cleaved upon treatment with TFA. The resin was filtered andwashed with DCM. The filtrate array was concentrated in vacuo anddissolved in DCM, and treated with pyridine (20 equivalents) and aceticanhydride (10 equivalents) for 30 min. A plurality of oxazolidinones wasprovided upon concentration of the solution array in vacuo.

Preparation of N-[(3-phenyl-2-oxo-5-oxazolidinyl)methyl]acetamide (22a).

To epoxide resin 12a (100 mg) in ACN at room temperature was added LiOTf(50 mg, 0.32 mmol) followed by aniline (61 μL, 0.66 mmol). After 16 hrs,the mixture was filtered and the resin sequentially washed with ACN andDMF. The resin (50 mg) in DMF (0.5 mL) was treated with CDI (27 mg, 0.17mmol) and NMM (50 μL) to provide resin bound oxazolidinone 20a. Themixure was allowed to stand for 2 hours, after which the resin wasfiltered and sequentially washed with DMF and DCM. The resin was treatedwith TFA (90% in DCM, 1 mL) for lh, filtered and washed with DCM. Thefiltrate was concentrated in vacuo to provide a residue (21a). Theresidue was treated for 1 h at 0° C. with triethylamine (18 μL, 0.13mmol) and acetyl chloride (10 μL, 0.13 mmol). In vacuo concentration ofthe reaction mixture provided crude product, which was purified bysemi-preparative HPLC to give oxazolidinone 22a (3.6 mg).

Direct Preparation of Oxazolidinone 20a.

To a solution of N-phenyl O-benzyl carbamate (152 mg, 0.67 mmol) in THF(2 mL) at −78° C. was added n-butyl lithium (1.5 M, 0.6 mL, 0.9 mmol).After stirring for 10 min, epoxide resin 12a (100 mg) was added to thereaction mixture. The mixture was allowed to warm to room temperatureand stirred overnight. Saturated ammonium chloride solution was added tothe reaction mixture. The resin was filtered and sequentially washedwith water, DMF and DCM. A portion of the resin was treated with TFA(90% in DCM, I mL) to cleave the oxazolidinone, which was isolated uponin vacuo concentration.

Preparation ofN-[(3-(4-bromophenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide

To epoxide resin 12a (300 mg) in ACN (2 mL) at room temperature wasadded LiOTf (219 mg, 1.41 mmol) followed by 4-bromoaniline (0.5 g, 2.9mmol). The reaction mixture allowed to stand overnight. The resin wasthen filtered, washed sequentially with ACN, DMF and DCM and dried invacuo. The resin (230 mg) was suspended in DMF (2 mL) at roomtemperature and treated with CDI (125 mg, 0.77 mmol) and NMM (84 μL,0.77 mmol). After shaking overnight, the resin was filtered andsequentially washed with DMF and DCM. To a portion of the resin (20 mg)was added TFA (50% in DCM, 1 mL) at room temperature and the resultingmixture was stirred for 30 min. The resin was filtered and washed withDCM. The filtrate was concentrated in vacuo to provide a residue. Aceticanhydride (0.1 mL) and pyridine (0.1 mL) were added to the residue inDCM (2 mL). The mixture was concentrated and purified bysemi-preparative HPLC to giveN-[(3-(4-bromophenyl)-2-oxo-5-oxazolidinyl)methyl]-acetamide (2 mg, 41%theoretical yield). ¹H NMR.

Preparation ofN-[[3-(3-fluoro-4-moroholinylphenyl)-2-oxo-5-oxazolidinyl]-methyl]acetamide(28a)

To epoxide resin 5a (100 mg) in ACN (1.0 mL) at room temperature wasadded LiOTf (78 mg, 0.5 mmol) followed by 3-fluoro-4-morpholinylaniline(197 mg, 1.0 mmol). The reaction mixture was allowed to stir overnight.The resin was then filtered, sequentially washed with ACN, DMF and DCMand dried in vacuo. A portion of the resin (25a) was suspended in DMF(0.8 mL) and treated with CDI (60 mg, 0.38 mmol) and NMM (100 μL, 0.91mmol). After shaking overnight, the resin was filtered and washedsequentially with DMF and DCM. To a portion of the resin (26a, 48 mg)was added TFA (90% in DCM, 1 mL) and the resulting mixture was allowedto stand for 1 h. The resin was filtered and washed with DCM. Thefiltrate was concentrated in vacuo to provide a residue. Acetyl chloride(12 μL, 0.17 mmol) and triethylamine (37 μL, 0.268 mmol) were added tothe residue in DCM (2 mL) at 0° C. The mixture was concentrated andpurified by semi-preparative HPLC to giveN-[[(3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide28a (1.8 mg, 15% theoretical yield). ¹H NMR.

Preparation ofN-[[3-(4-fluoro-2-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]-acetamide.To epoxide resin 12a (50 mg) in methanol (0.5 mL) was added4-fluoro-2-morpholinylaniline (50 mg, 0.255 mmol). The reaction mixturewas heated to 60° C. overnight and then allowed to cool to roomtemperature. The resin was filtered, sequentially washed with methanoland DCM and dried in vacuo. To the resin in DMF (0.5 mL) was added CDI(25 mg, 0.15 mmol) and NMM (50 μL, 0.45 mmol). The reaction mixture wasshaken for 4 hrs. The mixture was filtered, and the resin wassequentially washed with DMF and DCM. A portion of the resin (19 mg) wastreated with TFA (90% in DCM, 1 mL) for 1 h. The reaction mixture wasfiltered, and the resin was washed with DCM. The filtrate wasconcentrated to provide a residue. The residue was dissolved in DCM (2mL) and treated with pyridine (100 μL) and acetic anhydride (100 μL) atroom temperature for 1 h. The mixture was concentrated in vacuo andpurified by semi-preparative HPLC to giveN-[[3-(4-fluoro-2-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide(1.8 mg, 36% theoretical yield). ¹H NMR.

Attachment of Amine 32a to a solid support. To dry Peg HS HCl resin (30g, Perseptive Inc.) was added DIEA (30% in DCM, 150 mL). The mixture wasstirred at room temperature for 30 min. The resin was filtered,sequentially washed with DCM, methanol and DCM and dried in vacuo. To 30g. (18 mmol) of the resin in DMF (80 mL) were added Bal Linker 30a (8.04g, 1.7 eq., Perseptive Inc.), HATU (11.3 g, 1.6 eq.) and DIEA (18 mL,3.5 eq.). The reaction mixture was allowed to stand overnight at roomtemperature. The mixture was filtered and the resin was sequentiallywashed with DMF, MeOH, DCM and TMOF. To the resin was added amine 32a(18.2 g, 3 eq.) in 100 mL of TMOF. The mixture was stirred for 1 h,after which 50 mL of a NaBH₃(CN)-THF solution (1 M) was added. Thereaction mixture was stirred for 30 min., filtered and sequentiallywashed with methanol and DCM. In vacuo concentration of the filtrateafforded amine resin 33a. Cleavage of a portion of the resin with TFAprovided a 70% theoretical loading yield (0.6 mmol/g) of amine 32a. ¹HNMR.

Preparation of amides derived from amine 33a. To amine resin 33a (25 mg)in DMF (1 mL) at room temperature was added a solution of carboxylicacid (0.5 mmol) and diisopropylcarbodiimide (0.25 mmol). After 16 hrs,the reaction mixture was filtered, and the resin 36a was sequentiallywashed with DMF and DCM. The resin was treated with TFA (90% in DCM) toprovide the free amide 37a, which was obtained upon filtration and invacuo concentration. HPLC and MS analysis of the amide residue showedthat it was of greater than 80% purity.

Preparation of sulfonamides derived from amine 33a.

To amine resin 33a (25 mg) was added a solution of sulfonyl chloride(0.5 mmol) in DCM at room temperature. After standing for 16 hrs, thereaction mixture was filtered, and the resin was sequentially washedwith DMF and DCM. The resin was treated with TFA (90% in DCM) to providethe free sulfonamide 35a, which was obtained upon filtration and invacuo concentration. HPLC and MS analysis of the amide residue showedthat it was of greater than 80% purity.

Preparation of ureas derived from amine 33a.

To amine resin 33a (25 mg) was added a solution of isocyanate (0.5 mmol)in DCM at room temperature. After standing for 16 hrs, the reactionmixture was filtered, and the resin was sequentially washed with DMF andDCM. The resin was treated with TFA (90% in DCM) to provide the freeurea 39a, which was obtained upon filtration and in vacuo concentration.HPLC and MS analysis of the amide residue showed that it was of greaterthan 80% purity.

Preparation of Phenylsulfide Derivatives from Amine 33a

To amine resin 33a was added a solution of bromoacetic acid (3 eq.) andDIC (1.5 eq.) in DMF at room temperature. After 16 hrs, the reactionmixture was filtered to provide the bromoacetyl derivative 40a. Theresin was sequentially washed with DMF and DCM and dried in vacuo. Tothe resin (50 mg) in DMF was added potassium carbonate (50 mg) andthiophenol (0.5 mmol). The mixture was shaken overnight, filtered andsequentially washed with DMF, water, DMF and DCM. The resin was treatedwith TFA (90% in DCM) to afford the sulfide (5.0 mg, 40% theoreticalyield).

Method of Wittig Reaction from Acetyl Bromide 40a

To the bromoacetyl resin (40, 50 mg) in DMF (1 mL) was addedtriphenylphosphine (10 equivalents). After 16 hrs at room temperature,the resin was washed with DMF, and treated with potassium carbonate (20equivalents) and benzaldehyde (10 equivalents) for 16 hrs at roomtemperature. The resin was washed with DMF, water, DMF and DCM, andcleaved with TFA (50% in DCM) to give(S)—N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]cinnamamide(44): ¹H NMR (300 MHz) 7.62 (d, J=15.6 Hz, 1H), 7.54-7.33 (m, 6H), 7.09(d, J=8.8 Hz, 1H), 6.94 (t, J=9.2 Hz, 1H,), 6.53 (d, J=15.6 Hz, 1H,),4.87-4.82 (m, 1H), 4.08 (t, J=9.0 Hz, 1 H), 3.86 (t, J=4.2 Hz, 4 H),3.84-3.63 (m, 3H), 3.05 (t, J=4.2 Hz, 4H); MS (m/z) 426 (M⁺+1).

Arylsulfide Library

To an array of individual reaction chambers each containing particles orbeads of bromoacetyl resin 40a in DMF is added potassium carbonate and athiol unit at room temperature. The thiol units designated in Table Iare used. The array is shaken for 10 hrs, filtered and sequentiallywashed with DMF, water, DMF and DCM. The thio alcohol resin is cleavedupon treament with TFA. The resin is filtered and washed with DCM. Aplurality of sulfides is provided upon concentration of the filtratearray in vacuo.

Preparation of an Amide Library Derived from Amine 33a

To an array of individual reaction chambers each containing particles orbeads of amine resin 33a in DMF was added a solution of a carboxylicacid unit and diisopropylcarbodiimide. The carboxylic acid unitsdesignated in Table 4 were used. The array was shaken at roomtemperature for 16 hrs, filtered and sequentially washed with DMF andDCM. The amide resin was cleaved upon treament with TFA. The resin wasfiltered and washed with DCM. A plurality of amides was provided uponconcentration of the filtrate array in vacuo.

Preparation of a Sulfonamide Library Derived from Amine 33a

To an array of individual reaction chambers each containing particles orbeads of amine resin 33 in DCM was added a solution of a sulfonylchloride unit. The sulfonyl chloride units designated in Table 3 wereused. The array was allowed to stand for 16 hrs. It was then filteredand sequentially washed with DMF and DCM. The sulfonamide resin wascleaved upon treatment with TFA. The resin was filtered and washed withDCM. A plurality of sulfonamides was provided upon concentration of thefiltrate array in vacuo.

Preparation of a Urea Library Derived from Amine 33a

To an array of individual reaction chambers each containing particles orbeads of amine resin 33a in DCM was added a solution of an isocyanateunit. The isocyanates of Table 3 were used. The array was allowed tostand for 16 hrs. It was then filtered and sequentially washed with DMFand DCM. The urea resin was cleaved upon treatment with TFA. The resinwas filtered and washed with DCM. A plurality of ureas was provided uponconcentration of the filtrate array in vacuo.

Preparation of an Amide Library using the Amine Units in FIG. 30

To an array of individual reaction chambers each containing particles orbeads of aldehyde functionalized resin 31a is added an amine subunit inTMOF. The subunits listed in FIG. 30 are used. The mixture is stirredfor 1 h, after which a NaBH₃(CN)-THF solution is added. The reaction isstirred for 30 min., filtered and sequentially washed with methanol andDCM. In vacuo concentration of the filtrate affords the respective amineresins. The respective amine resin is placed in an array of individualreaction chambers. To the individual reaction chambers is added asolution of a carboxylic acid unit and diisopropylcarbo-diimide. Thecarboxylic acid units designated in Table 4 are used. The array isshaken at room temperature for 16 hrs, filtered and sequentially washedwith DMF and DCM. The amide resin is cleaved upon treatment with TFA.The resin is filtered and washed with DCM. A plurality of amides isprovided upon concentration of the filtrate array in vacuo.

Preparation of an Amide Library using the Amine Units in FIGS. 29, 30,and 31

To epoxide resin 7a (X═NH) in DMF is added a solution of a carboxylicacid unit and diisopropylcarbodiimide. The carboxylic acid unitsdesignated in Table 4 are used. After 3 hours, the resin is filtered,sequentially washed with DMF and DCM, and dried in vacuo. The respectiveresin is placed in an array of individual reaction chambers. To theresin in CAN in the individual reaction chambers is added LiOTf followedby an amine unit. The amine units shown in FIGS. 29, 30, and 31 areused. The array is shaken at room temperature for 15 hours, filtered andsequentially washed with CAN and DMF. To the array of amino alcoholresins is added NMM (10 equivalents) and CDI (5 equivalents). The arrayis shaken at room temperature for 10 hours, filtered and sequentiallywashed with DMF and DCM. The oxazolidinone resin is cleaved upontreatment with TFA. The resin is filtered and washed with DCM. Aplurality of oxazolidinones is provided upon concentration of thesolution array in vacuo. (The amines of FIGS. 29, 30, and 31 can be madeaccording to procedures described in the following publications: U.S.Pat. Nos. 4,948,801; 4,705,799; 5,164,510; 4,975,538; 5,225,565;5,182,403; 5,247,090; 5,231,188; 4,461,773; EP 0 785 201 A1; WO97/19089; DE 196 01 265 A1; WO 97/27188;EP 0 789 026 A1;DE 196 01 264A1; DE 196 04 223 A1; WO 97/30995; WO 97/09328; Van Delft et al. (1997)Synthesis 450-454; Wang et al. (1989) Tetrahedron 45:1323-1326; andDenis et al. (1994) Bioorg. & Med. Chem. Lett. 4:1925-1930; which arehereby incorporated by reference.)

Assay Protocol for β-Lactamase Inhibition. The lactamase (20-120 ng/mL)was incubated with a potential inhibitor with 1% DMSO in 50 mM potassiumphosphate buffer, pH 7.0, with 0.005% Brij-35 for 30 min at roomtemperature. 100 μM of nitrocefin was then added to the reaction mixtureand the hydrolysis of the nitrocefin was monitored by measuring theabsorption increase at 490 nm. Inhibition of the potential compounds wascalculated by comparing the rate of absorption increase with the controlsample which containing the identical mixture except inhibitors. TheIC₅₀, was obtained by fitting the inhibition data into a standard2-parameter IC₅₀ equation with a non-linear least-square fitting program(DeltaGraph).

Assay Protocol for Antimicrobial Activity. Minimum inhibitoryconcentrations (MICs) were determined using the microdilution method in96-well format plates. Compounds were suspended in DMSO at 5 or 10 mg/mland stored at 4° C. until used. They were diluted in Mueller-HintonBroth (MHB) or Trypticase Soy Broth (TSB) and used for MICdetermination. The range of concentrations tested was 64-0.0625 μg/mlfinal concentration using a two-fold dilution system.

The inoculum was prepared from cells grown on Trypticase Soy Agar (TSA)and incubated overnight at 35° C., 5 to 10 colonies were used toinoculate MHB or TSB broths, and the culture was incubated overnight at35° C. The overnight culture was diluted 1:10, incubated for one hour at35° C., diluted to the appropriate inoculum size and applied to thewells containing broth and test compound. Inoculum sizes were 1×10⁵ to5×10⁵ CFU/ml. Strains used included P. aeruginosa VPAE 1001, E. faeciumV VEFA 1001, E. faecium VanA VEFA1002, S. aureus VSAU1003, S. aureusMRSA VSAU1004, E. coli VEC05, and E. coli (arc-) VEC05.

Plates were incubated at 35° C. for 48 hours and MIC were recorded after18 hours of incubation, for bacteria, and 48 for yeasts. MIC was definedas the lowest concentration of compound that does not produce visiblegrowth after incubation.

Antimicrobial Activity for Representative Compounds in Animals

In vivo data was obtained for representative compounds i, ii, and iii todemonstrate the practical utility of the oxazolidinone compounds fortreatment of a bacterial infection in animals.

CD1 female mice (Charles River Laboratories) weighing 18-22 grams wereinjected intraperitoneally with 0.2 ml of a suspension containing 3*10⁷cfu of S. aureus (Smith strain) in 7% hog gastric mucosa (mucin). Themice were treated, either intravenously (i.v.) or orally (p.o.), 1 h and5 h after infection. Five groups of six mice each were given differentdosage levels representing two-fold dilutions of each compound (range of25 mg/kg—1.56 mg/kg). The compounds were all formulated in 40% aqueoushydroxypropyl-beta-cyclodextrin in PBS and untreated controls were dosedwith vehicle alone.

Mortality in each group was monitored daily for 6 days and cumulativemortality was used to determine the 50% protective doses (PD₅₀) whichwere calculated using the method of Reed and Muench [(a) Lorian, V.Antibiotics in laboratory medicine. Baltimore: Williams & Wilkins. 1996,p. 635-636; (b) Reed, L. J.; Muench H. A simple method of estimatingfifty percent endpoints. Am. J. Hyg. 1938, 27, pp. 493-497] (Table 1).For animals receiving vehicle alone, there was a 79% mortality rate(19/24) in the p.o. dosing group and an 88% mortality rate (15/17) inthe i.v. group; giving a total mortality rate for untreated controls of83%.

PD₅₀ for above compounds was in a range 2.3-7.2 mg/kg for i.v.administration and 7.5-14.9 mg/kg for p.o. administration, with compoundiii being the most preferred. TABLE 1 Thiols 2-mercaptobenzothiazole2-mercapto-4-methylpyrimidine HCl 2-mercaptothiazoline2-mercaptopyridine 2-mercapto-(3H)-quinazoline 2-mercapto-1-methylimidazole 5-(methylthio)-1,3,4-thiodiazole-2-thiol2-mercapto-6-thien-2-yl-4-(trifluoromethyl)pyridine-3-carbonitrilethiazolo[4,5-b]pyridine-2-thiol 4-(4-methoxyphenyl)pyrimidine-2-thiol2-mercapto-3-(trifluoromethyl)pyridine4,6-dimethyl-2-mercaptopyridine-3-carbonitrile4-trifluoromethylpyrimidine-2-thiol ethyl3-cyano-2-mercapto-6-methylpyridine-4-carboxylate2-mercapto-5-(trifluoromethyl)pyridine 5-chloro-2-mercaptobenzothiazole4-methyl-4H-1,2,4-triazole-3-thiol 2,4,6-trimethylbenzylmercaptan2-quinolinethiol 8-quinolinethiol HCl3-chloro-5-(trifluoromethyl)pyridine-2-thiol7-trifluoromethyl-4-quindine-thiol 2,4,6,-trichlorobenzenethiol5-[3-(trifluoromethyl)benzylthio]-1,3,4-thiadiazole-2-thiol4-(4-chlorophenyl)pyrimidine thiomalic acid 2,6-dichlorobenzenethiol4-hydroxythiophenol 5-(4,5-dichloroimidazole) 3-mercaptopropionic acid3,4-dichlorobenzenethiol 2,6,-dichlorobenzenethiol 2-methoxybenzenethiol2-bromothiophenol 4-fluorothiophenol4-bromo-2-(trifluoromethoxy)benzenethiol 3-(trifluoromethyl)benzenethiolthiolactic acid 3,4-dimethoxybenzenethiol 4-methoxybenezenethiol2-(trifluoromethyl)benzenethiol 4-(trifluoromethoxy)benzylthiol

TABLE 2 Amines 4-iodoaniline 2-iodoaniline 4-phenoxyaniline3-trifluoromethylamine m-anisidine o-anisidine 2-trifluoromethylaniline3-chloroaniline 1,4-benzodioxane-6-amine 5-aminoindan3,4-(methylenedioxy)-aniline 3-phenoxyaniline 4-morpholinoaniline4-amino-1-benzyl-piperidine 2-Bromoanaline 3-fluoroanaline4-trifluoromethoxyaniline 4-methylymercaptoaniline 3-bromoaniline2-fluoroaniline 4-fluoroaniline 2,4-difluoroaniline 3,4-difluoroaniline2,5-difluoroaniline 1-amino-5,6,7,8,-tetrahydronapthalene3,5-difluoroaniline 3-fluorobenzylamine 4-fluorobenzylamine4-aminoacetophenone 4-aminobenzophenone 3-benzyloxyaniline1-(3-aminopropyl)imidazole 4-(2-aminoethyl)-morpholine m-phenetidine3-chloro-4-fluoroaniline 2-bromo-5-(trifluoromethyl)aniline2-amino-3-benzyloxypyridine 2′-aminoacetophenone 4-aminobenzoic acid4-aminobiphenyl 3′-aminocetophenone 4-(3′-aminopropyl)morpholineaminopyrazine 2-aminopyridine 3-aminopyridine 4-aminopyridine6-aminoquinoline 8-aminoquinoline 4-aminoveratrole4-bromo-2,6-difluoroaniline 4-bromo-2-fluoroaniline4-bromo-3-(trifluoromethyl)aniline 4-bromo-3-methylaniline2-bromo-4-fluoroaniline 2-bromo-4-methylaniline 3-bromo-4-methylaniline4-butoxyaniline 3-fluoro-4-methylaniline 4-aminoquinaldine2-chloro-4,6-dimethylaniline 2-chloro-4-aminotoluene2-chloro-4-fluoroaniline 4-chloroaniline 2,4-dibromo-6-fluoroaniline2,4-dibromoaniline 2,5-dibromoaniline 2,4-dichloroaniline2,5-dichloroaniline 3,4-dichloroaniline 3,5-dichloroaniline2,3-difluoroaniline N,N-dimethy-1,4-phenylenediamine5-fluoro-2-methylaniline 2-fluoro-4-iodoaniline 5-amino-2-methoxpyridine2-methylmercapto)-aniline sulfanilamide sulfisomidine p-bromoaniline2-(4-aminophenyl)-6-methylbenzothiazole 4-amino-4′-nitrodiphenyl sulfide3-aminophenol 4-aminophenol 4′-aminoacetanilide 3-aminobenzyl alcohol4-aminophenethyl alcohol 2-aminoanthraquinone 6-aminonicotinamide2-amino-6-fluorobenzothiazole 2-amino-5-(4-nitrophenylsulfone)thiazole2-amino-4-methoxybenzothiazole 2-amino-4-chlorobenzothiazole2-amino-5-bromothiazole HBr 2-aminothiazole 2-aminobenzothiazole2-amino-6-methoxybenzothiazole 2-amino-6-nitrobenzothiazole2-amino-4-methylbenzothiazole 2-amino-4-(4-chlorophenyl)thiazole2-amino-5,6-dimethylbenzothiazole 2-amino-6-methylbenzothiazole2-amino-6-chlorobenzothiazole 2-amino-6-ethoxybenzothiazole2-amino-5-nitrothiazole 2-amino-5-(ethylthio)-1,3,4-thiadiazole methyl3-amino-2-thiophene carboxylateN-[4-(4-aminobenzyl)phenyl)]-5-norbornene-2,3-dicarboximide2-amino-4-pheylthiazole HBr 2-amino-3,5-dichloropyridine2-amino-5-bromo-pyridine 2-amino-4-picoline 5-amino-2-chloropyridine2-amino-4,6-dimethylpyridine 2-amino-5-chloropyridine2-amino-2-chloropyridine 2-amino-5-picoline 2-amino-6-picoline9-aminoacridine 5-aminoisoquinoline 3-aminoquinoline2-amino-4,6-dimethylpyrimidine 1-aminoisoquinoline 5-aminoquinoline2-amino-4,6-dichloropyrimididine 3-amino-5,6-dimethyl-1,2,4-triazine2-amino-4-chloro-6-methylpyrimidine 2-amino-4-methylpyrimidine5-amino-3-methylisothiazole 2-amino-5-bromopyrimidine2-amino-4,6-dimethoxypyrimidine 2-amino-4-methoxy-6-pyrimidine4-amino-6-chloro-2-(methylthio)pyrimidine 2-amino-5-chlorobenzoxazole2-amino-5-trifluoromethyl-1,3,4-thiadizole 3-amino-5-methylisoxazole4-amino-2,1,3-benzothiadiazole 2-amino-1,3,4-thiadiazole3-amino-1-phenyl-2-pyrazolin-5-one 6-amino-1,3-dimethyluracil4-amino-1,2-naphthoquinone hemihydrate3-amino-1-(2,4,6-trichlorophenyl)-2-pyrazolin-5-one1-(2-aminophenyl)pyrrole N-(4-amino-2-methylphenyl)-4-chlorophthalimide2-amino-3-chloro-5-(trifluoromethyl)pyridine 2-amino-3-picoline2-amino-4-methyl-5-nitropyridine 2-amino-4-methylthiazole2-amino-5-ethyl-1,3,4-thiadiazole 2-aminopyrimidine3-aminocrotononitrile 3-amino-1,2,4-trizole 3-aminopyrazole4-amino-2,3,5,6-tetrafluoropyridine 4-aminopyrimidine5-amino-1-ethylpyrazole 5-amino-1-phenyl-4-pyrazolecarboxamide5-amino-3-methylisoxazole 5-aminouracile

TABLE 3 Sulfonyl chlorides and Isocyanates p-toluenesulfonyl chloride2,4-dichlorobenzenesulfonyl chloride 2-thiophenesulfonyl chloridestyrenesulfonyl chloride 2-methoxycarbonylphenyl isocyanate4-acetylphenyl isocyanate cyclohexyl isocyanate p-tolyl isocyanate

TABLE 4 Carboxylic acids pyruvic acid p-toluic acid o-tolylacetic acidphenylacetic acid trans-2-pentenoic acid methylthio acetic acid4-methoxycinnamic acid nonanoic acid 3-methoxypropionic acid4-methoxycyclohexanecarboxylic acid phenylpropiolic acid1-naphthylacetic acid pentafluoropropionic acid piperonylic acidN-(2-furoyl)glycine propionic acid 2,3,4,5,6-pentafluorophenylaceticacid 4-pentenoic acid octanoic acid 3-methoxyphenylacetic acid4-methylcinnamic acid methacrylic acid p-(dimethylamino)cinnamic acidphenylpyruvic acid nicotinic acid 2-methylcinnamic acid methoxyaceticacid phenoxybenzoic acid phenoxyacetic acid cyclopropanecarboxylic acidglycolic acid trans-3-hexenoic acid 4-(trifluoromethyl)mandelic acid2-(2-methoxyethoxy)acetic acid diphenylacetic acid2-bromo-4,5-dimethoxycinnamic acid 3,4-dihydroxyhydrocinnamic acid3-methoxycinnamic acid 4-chlorophenoxyacetic acid4-(4-nitrophenyl)butyric acid 3-(4-chlorobenzoyl)propionic acid2-(4-hydroxyphenoxy)propionic acid 2-chlorocinnamic acid2-biphenylcarboxylic acid 2-(4-chlorophenoxy)-2-methylpropionic acidbenzoylpropionic acid 3-(phenylthio)acrylic acid3,5-di-tert-butyl-4-hydroxycinnamic acid 4-bromobutyric acid4-bromomandelic acid decanoic acid 4-hydroxycinnamic acid2-nitrocinnamic acid 2,3,4-trifluorocinnamic acid homovanillic acid3-methoxycyclohexanecarboxylic acid 2-ethoxycinnamic acid2,5-difluorophenylacetic acid 4-fluorocinnamic acid2,6-difluorophenylacetic acid 3,3-diphenylpropionic acid cis-pinonicacid 2-fluorobenzoic acid cyanoacetic acid1,2,3,4-tetrahydro-2-naphthoic acidtrans-2-phenyl-1-cyclopropanecarboxylic acid 4-(4-methoxyphenyl)butyricacid 2-formylphenoxyacetic acid 3-(4-fluorobenzoyl)propionic aciddifluoroacetic acid 3-chlorobenzo[b]thiophene-2-carboxylic acid4-methoxybenzylidenecyanoacetic acid 1-adamantaneacetic acid1-adamantanecarboxylic acid 1-fluorencarboxylic acid (2-naphthoxy)aceticacid 1H-benzimidazole-5-carboxylic acid2-(2,4,5-trichlorophenoxypropionic acid) 3-hydroxycinnamic acid abieticacid isoxazole-5-carboxylic acid (4-chloro-o-tolyloxy)-butyric acid3-pyridylacetic acid alpha-methyl-2,4,5-trimethoxycinnamic acid2-chlorophenylacetic acid 3-fluorophenylacetic acid (S)-(+)-mandelicacid 2,4-difluorophenylacetic acid butyric acid 4-methoxyphenylaceticacid 4-ethoxyphenylacetic acid trans-2-hexenoic acid3,4-dihydroxycinnamic acid 2,3-dichlorophenoxyacetic acidS-benzylthioglycolic acid 3,4-(methylenedioxy)phenylacetic acid(alpha,alpha,alpha-trifluoro-m-tolyl) acetic acid3,4-difluorophenylacetic acid 2-furioic acid 4-acetylphenoxyacetic acid4-(3,4-dimethoxyphenyl)butyric acid cyclohexanepropionic acid7-methoxy-2-bezofuran carboxylic acid 2-(triflouromethyl)cinnamic acid2,4-dinitrophenylacetic acid 2,4-dichlorophenylacetic acid2-nitrophenylpyruvic acid iodoacetic acid acetic acid4-(2,4-dichlorophenoxy)-butyric acid 3-(3,4,5-trimethoxyphenyl)propionicacid 6-chloro-2H-1-benzopyran-3-carboxylic acid 4-acetamidocinnamic acid3-hydroxyphenylacetic acid 2-chloro-6-fluorocinnamic acid3-fluoro-4-hydroxyphenylacetic acid 4-fluorophenylacetic acidtrans-3-fluorocinnamic acid 3-bromocinnamic acid 2-pyridylacetic acidalpha-fluorocinnamic acid 4-(2-cyclohexenyloxy)benzoic acid 1-naphthoicacid 2-bromophenylacetic acid 4-nitrocinnamic acid 2-propylpentanoicacid 3,4-dihydro-2,2-dimethyl-4-oxo-2h-pyran-6-carboxylic acid3-(2-methoxyphenyl)propionic acid 2-fluorocinnamic acid tiglic acid(4-pyridylthio)acetic acid 4-hydroxyphenylacetic acid4-bromophenylacetic acid chloroacetic acid chromone-2-carboxylic acid4-bromocinnamic acid alpha-phenyl-cinnamic acid benzoylformic aciddichloroacetic acid 3,5-dimethoxy-4-hydroxycinnamic acidtrans-4-(trifluoromethyl) cinnamic acid cyclohexylacetic acidcyclopentylpropionic acid (−)-mentoxyacetic acidalpha-fluorophenylacetic acid 3-(3,4-dimethoxyphenyl)propionic acid3,4-dichlorocinnamic acid 4-fluorophenoxyacetic acid thiophenoxyaceticacid 3,5-bis(trifluoromethyl)phenylacetic acid (4-methylphenoxy)aceticacid 6-methylchromone-2-carboxylic acid (3,4-dimethoxyphenyl)acetic acid3-chlorophenylacetic acid 2,3,4,5,6-pentafluorocinnamic acid3-indolepropionic acid 2-thiopheneacetic acid6-bromocoumarin-3-carboxylic acid 4-pyridylacetic acidalpha-methylhydrocinnamic acid alpha-phenylcinnamic acidcis-2-methoxycinnamic acid 4-phenylcinnamic acid 4-chloro-o-anisic acid4-ethoxycinnamic acid 2-phenylpropionic acid3,4-(methylenedioxy)cinnamic acid 1-phenyl-1-cyclopropanecarboxylic acid3-cyanobenzoic acid 3,4,5-trimethoxyphenylacetic acid(2-amino-thiazole-4-yl)acetic acid 2,3-dimethoxybenzoic acid4-chorophenylacetic acid bis(4-chlorophenoxy)acetic acidtetrahydro-2-furoic acid trans-styrylacetic acid 4-chlorocinnamic acidalpha-methylcinnamic acid alpha-cyanocinnamic acid 4-methylvaleric acid4-pyrazolecarboxylic acid 2-fluorophenylacetic acid3-(1-naphthyl)acrylic acid 3-bromophenylacetic acidalpha-cyano-3-hydroxycinnamic acid 2-(3-chlorophenoxy)propionic acid2,5-dimethylcinnamic acid 2,6-dichlorophenylacetic acid3-phenoxypropionic acid 2,6-dichlorocinnamic acid(2,5-dimethoxyphenyl)acetic acid 2,3,4-trimethoxycinnamic acid2,3,4-trimethoxybenzoic acid 2-chlorobenzoic acid3,4,5-trimethoxycinnamic acid cyclobutanecarboxylic acidcyclohexene-1-carboxylic acid 4-nitrophenylacetic acid benzoylbutyricacid 3,5-dimethoxybenzoic acid alpha-cyano-4-hydroxycinnamic acidcyclopentanecarboxylic acid 5-(pyrid-2-yl)thiophene-2-carboxylic acidbromoacetic acid trans-4-hydroxy-3-methoxycinnamic acid4-chloro-2-fluorocinnamic acid 2-octynoic acid 3-(p-tolyl)propionic acid4-chlorobenzoic acid 2-methoxyphenylacetic acid 4-biphenylcarboxylicacid 2-chloro-4-fluorocinnamic acid 2-norbornameacetic acid2-naphthylacetic acid 2-methyl-1-cyclohexanecarboxylic acid(1-naphthoxy)acetic acid 2,5-dimethoxybenzoic acid cyclopentylaceticacid ethoxyacetic acid cyclohexanebutyric acid2-methylcyclopropane-carboxylic acid 4-methylcyclohexaneacetic acid4-hydroxymandelic acid monhydrate 4-bromo-2-fluorocinnamic acid lauricacid 2-bromovaleric acid 2,6-dimethoxybenzoic acidtrans-2,3-dimethoxycinnamic acid 3-(4-hydroxyphenyl)propionic acid3-(4-methoxybenzoyl)-propionic acid(alpha,alpha,alpha-tri-fluoro-p-tolyl)acetic acid hydrocinnamic acid3,4-difluorocinnamic acid 3,5-bis(trifluoromethyl)benzoic acid(3,5-dimethoxyphenyl)acetic acid 9-anthracenecarboxylic acid3-(trifluoromethyl)cinnamic acid m-tolylacetic acid 4-formylcinnamicacid 3-furic acid crotonic acid alpha-acetamidocinnamic acidalpha-phenylcyclopentaneacetic acid diphenylacetic acid4,5-dimethoxy-2-nitrocinnamic acid 4-(methylthio)phenylacetic acid3,5-dimethoxycinnamic acid 3-nitrocinnamic acid5-chlorobenzo[b]thiophene-3-acetic acid 3-methyl-2-phenylvaleric acid3-(trifluorometoxy)cinnamic acid 4-biphenylacetic acid3-bromo-4-fluorocinnamic acid 3-(2-hydroxyphenyl)propionic acid2,4-difluorocinnamic acid 5-methoxy-1-indanone-3-acetic acidalpha-methoxyphenylacetic acid 2-thiophenecarboxylic acid3-(4-methoxyphenyl)propionic acid 4-acetoxy-3-methoxycinnamic acid2-methoxycinnamic acid 3-benzoylbenzoic acid levulinic acid3,4-dichlorophenylacetic acid 3-methylindene-2-carboxylic acid4-phenoxybutyric acid 2-hydroxycinnamic acid 2-ethoxy-1-naphthoic acid2-chloro-5-nitrocinnamic acid 3,3-dimethylacrytic acid 4-pentynoic acid4-acetoxycinnamic acid 2-(p-toluoyl)-benzoic acid 3,5-difluorocinnamicacid 2-ethoxybenzoic acid trans-2-methyl-2-pentenoic acidcycloheptanecarboxylic acid tetrahydro-3-furoic acid3,5-difluorophenylacetic acid trans-2,6-difluorocinnamic acid thiocticacid 5-bromo-2-fluorocinnamic acid 11-phenoxyundecanoic acid2,4-dichlorophenoxyacetic acid 2-(2,4-dichlorophenoxy)-propionic acid2,2-dimethylbutyric acid o-tolulic acid2-bromo(4,5-(methylenedioxy)cinnamic acid alpha-bromophenylacetic acidtrans-N-(2-furfurylideneacetyl)-glycine 3-chlorobenzoic acidD-3-phenyllactic acid 2-phenoxybutyric acid 2-(4-chlorophenoxy)propionicacid 2-acetoxycinnamic acid (R)-(−)-mandelic acid(+−)-6-methoxy-alpha-methyl-2-naphthaleneacetic acid(+−)-2-(2-chlorophenoxyy)propionic acid (+/−) 2-phenyoxypropionic acid1-methyl-1-cyclohexanecarboxylic acid 2,5-dimethoxycinnamic acid2-(2-aminothiazole-4-yl-2-methoxyiminoacetic acid 2-acetamidoacrylicacid

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity andunderstanding, it will be apparent to those skilled in the art thatcertain changes and modifications may be practical. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compound of the structure 1b:

a its pharmaceutically acceptable salt thereof wherein R₂, R₃, R₄ and R₅are, independently, hydrogen alkyl, heteroalkyl, heteroaryl or anelectron withdrawing group; R₆ is acyl or sulfonyl; and, R₁ is one ofthe following functional groups: C(O)R₁₀, wherein R₁₀ is hydrogen,alkyl, heteroalkyl, aryl or heteroaryl; SR₁₁, wherein R₁₁ is hydrogen,alkyl, heteroalkyl, aryl or heteroaryl; S(O)₂R₁₁, wherein R₁₁ ishydrogen, alkyl, heteroalkyl, aryl or heteroaryl; S(O)R₁₁, wherein R₁₁is hydrogen, alkyl, heteroalkyl, aryl or heteroaryl; NR₁₂R₁₃, whereinR₁₂ and R₁₃ are, independently, hydrogen, acyl, sulfonyl, alkyl,heteroalkyl, aryl or heteroaryl; 2-oxazolyl, wherein R₁₄ is at the4-position and R₁₅ is at the 5-position of the oxazolyl, and wherein R₁₄and R₁₅ are, independently, hydrogen, alkyl, heteroalkyl, aryl,heteroaryl or an electron withdrawing group; 2-aminothiazolyl, whereinR₁₆ is at the 4-position and R₁₇ is at the 5-position of the thiazole,and wherein R₁₆ and R₁₇, are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl or an electron withdrawing group; andCH₂NR₁₈R₁₉, wherein R₁₈ and R₁₉ are, independently, hydrogen, alkyl,heteroalkyl, aryl, heteroaryl, acyl or sulfonyl.
 2. A compound accordingto claim 1 wherein R₁ is C(O)R₁₀.
 3. A compound according to claim 2wherein R₁₀ is aryl or heteroalkyl.
 4. A compound according to claim 1,wherein R₁ is SR₁₁.
 5. A compound according to claim 4 wherein R₁₁ isaryl or heteroalkyl.
 6. A compound of claim 1 wherein R₁ is S(O)₂R₁₁ orS(O)R₁₁.
 7. A compound according to claim 6 wherein R₁₁ is aryl.
 8. Acompound according to claim 7 wherein R₁₁ is heteroalkyl.
 9. A compoundof claim 1 wherein R₁ is NR₁₂R₁₃.
 10. A compound according to claim 1,wherein R₃, R₄ and R₅ are hydrogen; and R₂ is fluorine.
 11. The compoundof claim 1 which is


12. The compound of claim 1 which is


13. The compound of claim 1 which is


14. The compound of claim 1 which is


15. The compound of claim 1 which is


16. A method for treating or preventing an infectious disorder in ahuman or an animal comprising administering to the subject an effectiveamount of a compound of claim
 1. 17. A composition for the treating orpreventing of an infectious disorder in a human or an animal comprisingan effective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.